Methods and pharmaceutical compositions for the treatment of symptoms of anxiety and panic using beta adrenergic receptor antagonist and muscarinic receptor antagonist combinations

ABSTRACT

The present invention is focused primarily toward pro re nata (“as needed”) treatments for a psychiatric condition or disorder or the symptoms thereof, including the symptoms of acute anxiety and panic in living animals, including humans. The present invention encompasses pharmaceutical compositions as combination therapies containing at least one beta adrenergic receptor antagonist and at least one muscarinic receptor antagonist. The invention provides methods for treating psychiatric condition or disorder or the symptoms thereof, including acute anxiety and panic comprising administering a pharmaceutical composition consisting essentially of a beta adrenergic receptor antagonist drug and an antiemetic muscarinic receptor antagonist drug in a therapeutically effective amount to stop or reduce the symptoms of anxiety and/or panic. The pharmaceutical compositions are administered as treatments immediately in advance of, at the onset of, or during an acute anxiety and/or panic episode.

BACKGROUND OF THE INVENTION

In spite of the abundance and availability of numerous oral psychiatricpharmaceuticals, there is an unmet need in the pharmaceuticalmarketplace for fast-acting therapies for the pro re nata (p.r.n.; “asneeded”) treatment of symptoms of acute anxiety and panic. The presentinvention addresses multiple aspects of this unmet medical need via thefollowing beneficial features, among others.

The present invention is focused primarily toward p.r.n. treatments forthe symptoms of acute anxiety and panic. The same or similar treatmentsmay also provide benefit with regard to an even broader group ofpsychiatric conditions or disorders, such as alcohol addiction and/orwithdrawal, drug addiction and/or withdrawal, migraine, headache, andaggression. Effective treatments for the symptoms of acute anxiety andpanic per se should coincidentally reduce or remove some of the samesomatic and/or psychic symptoms associated with this broader group ofpsychiatric conditions.

The active pharmaceutical ingredient (API) combinations of the presentinvention provide complementary pharmacologic benefits by interaction oftwo types of APIs having two (or more) dissimilar pharmacologicmolecular targets. The biochemical pathways of the beta adrenergicreceptor and muscarinic receptor gene families are appropriateanxiolytic targets for the symptoms of panic attack (PA), panic disorder(PD), agoraphobia, generalized anxiety disorder, social anxiety disorder(social phobia), performance anxiety (e.g., stage fright),post-traumatic stress, post-traumatic stress disorder (PTSD),post-traumatic anxiety, and shell shock. These anxiety disorders arefurther delineated within the Diagnostic and Statistical Manual ofMental Disorders (e.g., DSM-5). Furthermore, these distinct biochemicalpathways may be appropriate for therapeutic intervention for drugaddiction and/or withdrawal, alcohol addiction and/or withdrawal,migraine, headache, and aggression. Those molecular targets can becomponents of the central nervous system (CNS), the peripheral nervoussystem, and/or of target somatic tissues (e.g., cardiovascular andgastrointestinal tissues). The appropriate combination of APIs isexpected to affect more molecular targets than could be achieved byusing a single API alone. Given that the multiplicity of symptoms of PA,PD, anxiety, and anxiety-related disorders are under the regulation ofdifferent neurologic, neuroendocrine, and endocrine pathways, it followsthat pharmacologic antagonists affecting both the beta adrenergicreceptors and muscarinic receptors could suppress more symptoms thancould be achieved by a single API alone.

An acute anxiety or panic attack “trigger” circumstance results in theautonomic release of epinephrine (adrenaline), as well as cortisol andnorepinephrine. This in turn causes multiple effects consistent with a“fight-or-flight response”. Symptoms include tachycardia (increasedheart rate), palpitations (perception of an elevated heart rate and/orof a strong heart beat), hypertension (increased blood pressure),hyperventilation (with reduced blood CO₂ and altered pH), dyspnea,mental anxiety, nausea, vomiting, fear, avoidance, trembling (tremors),sweating, headache, among others. Many of the somatic and/or psychic(CNS) symptoms of panic attack are shared in common with social anxietydisorder (social phobia), generalized anxiety disorder, agoraphobia, andPTSD. Therefore, it follows that an effective treatment for the symptomsof panic per se can also be effective against anxiety andanxiety-related disorders.

Some patients anticipate future episodes of panic or acute anxiety basedupon his/her history of encounters with a known “trigger” circumstance.A trigger circumstance might be public speaking, a public musicperformance, flying, driving, a noise, a crowd of people (e.g.,agoraphobia), decision-making, an unfamiliar setting, among others.Given the patients' anticipation of a trigger leading toward likelyfuture symptoms, p.r.n. drug treatments of the present invention can bedesigned for rapid effect, and with the pharmacologic benefits beginningeither during or immediately prior to the time when symptoms would beexpected to commence.

The lifetime prevalence of PA is 28.3% of the adult US population [1].The 12-month prevalence of panic disorder (PD) is estimated to be 2.7%of the adult US population [2], with 1.2% considered as “severe” [3].More than half of affected adults (59.1% or ˜3.8 million) are receivingtreatment(s) [4]. Patients affected by PAs are often also affected bythe co-morbid conditions of depression [5] and migraines (and otherforms of headaches) [6, 7]. In aggregate panic and anxiety are extremelycommon, affecting nearly 40 million in the US.

The current standards-of-care for PD are oral psychiatric prophylacticpharmaceuticals, including: (1) Selective serotonin reuptake inhibitors(SSRIs), which are considered as the first choice medicines for PD.Examples include Paroxetine (PAXIL®), Sertraline (ZOLOFT®), andFluoxetine (PROZAC®); (2) Benzodiazepines, such as Clonazepam(KLONOPIN®), Alprazolam (XANAX®), Lorazepam (ATIVAN®)), and Diazepam(VALIUM®); (3) Serotonin-norepinephrine reuptake inhibitors (SNRIs),such as Duloxetine (CYMBALTA®) and Venlafaxine (EFFEXOR®); and (4) othermedications, such as Quetiapine (SEROQUEL®), an antipsychotic prescribedfor generalized anxiety disorder. These oral therapies are taken dailyfor the prevention of panic attacks. Some of these drugs are FDAapproved for the prophylaxis of PD, such as Paroxetine, Sertraline,Alprazolam, and Clonazepam.

Other anxiety-related disorders are also treated in the same or asimilar manner. For instance, social anxiety disorder (social phobia),generalized anxiety disorder, agoraphobia, and post-traumatic stressdisorder (PTSD) are also treated using the same or similar oral dailypharmaceutical regimens [8].

The pharmaceutical standards-of-care in routine psychiatric care of PA,PD, anxiety, and anxiety-related disorders involve two key aspects: (1)prophylaxis, rather than treatment of the symptoms per se; and (2) themedications are routinely given as daily oral “maintenance” medicationsfor persistent use (i.e., chronic prophylaxis), rather than asoccasional administration “as needed” (p.r.n.) at the time of episodesof symptoms (i.e., acute therapy). The present invention provides analternative paradigm that goes beyond the current standards-of-care inpsychiatric medicine for PA, PD, anxiety, and anxiety-related disorders.

Although oral benzodiazepines have been used as persistent dailymedications for the prophylaxis of panic and acute anxiety, they are notreasonable candidates for this alternative “fast-acting” p.r.n. approachof the present invention. Although benzodiazepines are often mistakenlyconsidered to be “fast-acting”, multiple clinical reports indicateotherwise. Zamorski and Albucher stated, “Benzodiazepines should not beused on an as-needed basis for panic disorder. None of the oralbenzodiazepines works quickly enough to affect any but the mostprolonged panic attacks.”[9] Altamura and coworkers stated recently, “ .. . it would be desirable for the development of new anxiolytic drug(s)that are more selective, fast acting and free from the unwanted effectsassociated with the traditional benzodiazepines as tolerance ordependence.”[10] Altamura and coworkers also stated regardingbenzodiazepines as a class of anxiolytic drugs, “Only lorazepam iscurrently available in a form suitable for sublingual administration,which was developed in the hope that, by bypassing the gut, a more rapidonset could be achieved similar to that with intramuscularadministration. However, Greenblatt et al. [11] found that thesublingual formulation was absorbed at a rate that did not differsignificantly from that of regular oral administration of the standardtablets or even from that of sublingual administration of the standardoral tablets.” [10] Thus, benzodiazepines are not suitable for rapidtreatment of symptoms of panic attacks or acute anxiety episodes, evenwhen delivered sublingually (mucosally). In conclusion, when “time is ofthe essence” for therapy, benzodiazepines are inadequate, regardless ofthe oral or sublingual routes of administration.

Furthermore, SSRIs are considered as the first choice medications for PDprophylaxis, but they require a very slow dose-escalation approach overweeks of time to produce a beneficial effect. Thus, the most commondrugs for the indications that are the focus of thisinvention—benzodiazepines and SSRIs—are not feasible for p.r.n. therapyfor rapid symptomatic relief.

Benzodiazepine and SSRI drugs can produce disabling psychic and somaticside effects, such as sedation, lethargy, chemical dependence,tolerance, and sexual dysfunction[9]. As a result of these negative sideeffects and potential for abuse, benzodiazepines are classified by theU.S. Food and Drug Administration (FDA) as Schedule 4 (IV) “ControlledSubstances”. Many physicians and other prescribers (e.g., dentists) arereluctant or prohibited from prescribing benzodiazepines. The presentinvention does not include either benzodiazepines or SSRIs as APIs. Noneof the APIs of the present invention are “Controlled Substances” asclassified by the U.S. FDA Schedules 1-4.

The present invention encompasses pharmaceutical compositions ascombination therapies containing at least one beta adrenergic receptorantagonist (e.g., propranolol, atenolol, or nadolol) and at least onemuscarinic receptor antagonist (e.g., scopolamine, diphenhydramine, ormeclizine). In an embodiment, a representative combination therapy ofinterest includes two well-known APIs, scopolamine and a beta blocker,such as propranolol.

Coma et al. (US Application Publication No. 2013/0116215) describecombinations of compounds which are therapeutically effective fortreating neurodegenerative disorders. The application refers in generalto methods of a “Therapeutic Performance Mapping System” technology. Theapplication does not specifically disclose a combination of propranololand scopolamine for the treatment of neurodegenerative diseases.Moreover, the application does not relate to the treatment of PA and PD.

Dargelas et al. (US Application Publication No. 2009/0220611) disclosemicroparticulate systems with modified release of oral activeprinciple(s). The application explains that “coated ‘reservoir’microparticles” may be used in the treatment of a lengthy list ofmedical indications, including cardiovascular and nervous systemconditions among others, and discloses a lengthy list of APIs, forexample, scopolamine or propranolol, which may be coated and formulatedas microparticles.

Arora et al. (US Application Publication No. 2011/0281853) and Zembower& Arora (PCT International Publication No. WO 2011/143457) disclosecompositions and methods for treating or preventing atrial fibrillation(AF). In particular, the application discloses administration ofmuscarinic receptor antagonists (e.g., M2-selective muscarinic receptorblockers), alone or in combination with other therapeutic agents (e.g.,beta adrenergic receptor blockers), to treat and/or prevent atrialfibrillation. Arora et al. are silent with respect to compositions andmethods for treating symptoms associated with PA, PD, anxiety,anxiety-related disorders, or psychiatry in general.

Kukkonen-Harjula and coworkers [12] discloses the cardiovascular effectsof oral atenolol, oral scopolamine, or a coincident administration ofboth drugs in healthy volunteers prior to and during exposure to heatwithin a sauna. However, this article does not address pharmaceuticalcompositions and methods for treating PA, PD, anxiety, anxiety-relateddisorders, or psychiatry in general.

Frenette et al. (PCT International Publication No. WO2012/071573)disclose the use of beta adrenergic receptor antagonists (e.g.,propranolol) and muscarinic receptor antagonists (e.g., scopolamine)among a lengthy list of APIs for use as cancer chemotherapies,specifically to inhibit tumor initiation and tumor metastasis.

Holly (US Application Publication No. 2011/0218215) disclosescompositions and methods for treating social anxiety including a betaadrenergic receptor antagonist (specifically propranolol) coupled withan antidiarrheal agent (specifically the opioid diphenoxylate). Thecompositions may optionally include an anticholinergic agent(specifically atropine sulfate), but this is not required. And, theanticholinergic, atropine, is intended to deter abuse in the event of anoverdose, rather than an efficacious benefit toward social anxiety.Unlike Holly, the present invention requires the inclusion of ananticholinergic agent, and does not require or envision an antidiarrhealagent. Furthermore, Holly is not directed toward PA or PD as therapeuticindications.

Chow et al. (U.S. Pat. No. 8,012,503) claim a method for enhancingabsorption involving a mathematical calculation to derive a theoreticalpH for a single API intended for administration to the oral mucosa.Scopolamine and propranolol are disclosed in a lengthy list of APIs forwhich a theoretical pH may be derived according to the mathematicalcalculation of the invention.

Hsiao et al. (U.S. Pat. No. 4,755,386) disclose a buccal-adhesive drugdelivery technology. Both propranolol and scopolamine are included in alengthy list of APIs, which may be included as single agents in thebuccally-delivered adhesive composition of the invention.

The present invention is focused primarily on fast-acting, mucosally-and orally-delivered pharmaceutical compositions for p.r.n. (“asneeded”) treatment of symptoms of panic and acute anxiety, or inanticipation of the symptoms in patients. The compositions consistessentially of an antiemetic antimuscarinic drug and a beta adrenergicreceptor antagonist drug, wherein the antimuscarinic drug may bescopolamine and the beta adrenergic receptor antagonist drug may beatenolol, propranolol, pindolol, nadolol, or nebivolol, among otherchoices.

The present invention is focused on the augmentation of a beta blocker'seffects on the cardiovascular system's symptoms of acute anxiety orpanic with an antiemetic antimuscarinic agent's effects onnon-cardiovascular symptoms of acute anxiety or panic. The term“anxiety” covers a vast breadth of definitions and symptoms. The presentinvention addresses all or most of the symptoms of acute anxiety orpanic episodes, neither of which is addressed by an “off-label” betablocker alone or an antiemetic antimuscarinic agent alone. The presentinvention can achieve desirable pharmacologic effects upon a diversearray of cardiovascular and non-cardiovascular symptoms at appropriatedoses of APIs that are antiemetic, non-sedating, fast-acting, andcoincidentally without the use of addictive drugs and/or ControlledSubstances as APIs. Furthermore, augmentation of a beta blocker (i.e.,cardiovascular effects) with an antiemetic agent that only affects thesymptoms of nausea, vomiting, and/or motion sickness per se providesanxiolytic superiority over a beta blocker alone or an antiemetic agentalone.

Propranolol is the most thoroughly studied of the beta blockers, andserves as the prototype for this class of drugs. Propranolol (or apharmaceutically acceptable salt thereof) is a beta adrenergic receptorantagonist to reduce cardiac symptoms (e.g., tachycardia andhypertension) resulting from epinephrine in the circulation. Betablockers interfere with receptor binding by catecholamines, epinephrineand norepinephrine, of which epinephrine is the principal catecholamineaffecting the cardiac symptoms. Propranolol is a lipophilic beta blockerthat readily crosses the blood-brain barrier. Therefore, it affects bothsomatic and CNS target tissues. Propranolol can be absorbed mucosally,as demonstrated by sublingual delivery [13], and its bioavailability ishigher when absorbed by this route rather than orally [14, 15]. Also,propranolol has been delivered by rectal administration in mammals [16].It does not demonstrate chemical dependence or sedation that are commonside effects of many psychiatric medications.

Propranolol is prescribed for the treatment of various cardiovascularindications (with U.S. FDA approval), most notably hypertension,arrhythmia, angina, as well as prophylaxis of migraines. However, thereis some evidence that it might also have some benefit with regard to asubset of the symptoms of panic and acute anxiety, although this isdisputed. The drug's anxiolytic potential was recognized as early as1966, “Emotions are expressed through the autonomic nervous system, andanxiety states are associated with increased secretion ofcatecholamines. Propranolol may therefore have a place in the treatmentof anxiety, especially when the symptoms are related to thecardiovascular system.” [17] This prescient comment five decades ago wassubsequently validated by clinical studies with regard to both aspects:(a) propranolol and other beta blockers have been used off-label in theUSA for the prophylaxis of performance anxiety; and (b) thepharmacologic benefits of propranolol and other beta blockers arerestricted to the cardiovascular system effects per se. The beneficialanxiolytic effects are limited to blocking the pharmacologic effects ofcatecholamines upon the cardiovascular system without addressing thepsychic (CNS) symptoms or other somatic symptoms of acute anxiety andpanic, with the possible exception of tremors.

Daily oral propranolol has been demonstrated in one prophylactic studyto suppress panic attacks in subjects diagnosed with panic disorder andagoraphobia [18]. Tyrer and Lader demonstrated some effectiveness oforal propranolol in treating somatic anxiety symptoms, but not psychic(mental) anxiety [19, 20]. Another daily oral prophylactic studycompared propranolol to oxprenolol and revealed that both beta blockersreduced symptoms of anxiety at one or two weeks duration [21]. However,propranolol was more effective at reducing palpitations when assessed onday 7 compared to oxprenolol. In another clinical study, daily oralpropranolol was not effective at treating panic disorder and agoraphobiawith panic attacks [22].

There is some evidence suggesting that propranolol might be beneficialin academic test-taking among normal and anxiety-prone students.Examination performance might be increased by pretreatment with thisbeta blocker [23, 24].

Propranolol has been further studied in clinical trials designed toprovoke anxiety. Using the Trier Social Stress Test (TSST) to provokeanxiety in a clinical setting, the somatic and psychic effects of oralpropranolol were tested in healthy adult volunteers [25-28]. Propranolol(40 mg) one hour prior to TSST significantly reduced heart rate, reducedsystolic blood pressure, and enhanced cognitive flexibility duringstress [26]. In another study, propranolol (80 mg) one hour prior toTSST significantly reduced heart rate and increased salivary cortisol,but did not significantly affect BP or subjective stress [25]. Inanother TSST study, daily oral propranolol (80 mg) did not affect thesalivary cortisol response [27]. In a study with healthy volunteersubjects using carbon dioxide inhalation to provoke panic and anxiety,propranolol significantly decreased heart rate, a somatic symptom, butdid not provide psychic anxiolytic benefit [29].

Propranolol has also been investigated in patients suffering from severeposttraumatic stress disorder (PTSD). Two clinical studies of this betablocker have shown possible benefits in the early-stage interventionalprevention and subsequent therapy of PTSD [30, 31]. Subsequent reportshave also echoed that propranolol might be effective for this condition[32-34], although other reports dispute this conclusion [35, 36].

When considered in aggregate these clinical studies of propranolol, as awell known prototypical beta blocker, provide convincing evidence thatthe drug can exert somatic (i.e., peripheral) effects on thecardiovascular system in the context of panic and anxiety. With regardto affecting the psychic (CNS) symptoms, the results have been negative,inconsistent, or inconclusive. That being said, there is some limitedevidence that propranolol can exert some psychic (CNS) benefits inclinical stress trials. In a pair of clinical studies, propranolol (acentral and peripheral beta-blocker) significantly enhanced problemsolving during stress, whereas nadolol (peripheral only beta-blocker)and lorezapam (benzodiazepine) did not [37, 38]. Thus, propranololenhanced cognitive flexibility (“creativity”) during stress. It remainsunclear whether propranolol alone can appreciably reduce psychic stress,thus the “need” to complement it with a dissimilar class ofpharmacologic agents (e.g., muscarinic receptor antagonists). Thus,augmentation of a beta blocker's limited scope of effects upon thediversity of symptoms of acute anxiety and panic by anotherpharmacologic class of agents (i.e., antimuscarinic agents) is anessential aspect of the present invention.

The designs of many, if not all, of these historic clinical studies ofpropranolol might not mirror the conditions of the intended use of thepresent invention.

Numerous alternative beta blockers are available in lieu of propranolol,for instance atenolol, nadolol, pindolol, and nebivolol, among otherchoices. One appealing alternative beta blocker is atenolol that hasbeen used to suppress stage fright in performers when administeredorally in advance [39]. Atenolol is a beta-1 selective peripheral-actingagent without CNS effects, which should reduce the risk for asthmaticsubjects [40]. Oral atenolol at 50-200 mg doses suppresses heart rate by˜23-24 beats per minute (bpm) vs. ˜10 bpm on placebo [40]. Also,atenolol has been delivered by a mucosal route in mammals [16]. Plus, itwas determined during development that sublingual formulations of thepresent invention containing atenolol do not have a taste and do notproduce mouth paresthesia in humans. The latter two properties areunanticipated advantages over the use of propranolol in sublingual doseforms.

Another alternative beta blocker is nadolol, which is non-selective witha preference for beta-1 receptors, and does not pass through theblood-brain barrier. In a clinical trial with musicians, nadolol reducedpulse rate and improved one aspect of performance related to tremor[41]. A similar result was obtained for nadolol in students' singingperformance [42]. In spite of being non-selective, nadolol mightironically benefit asthma patients based upon the appropriate dosage, ananti-intuitive result [43].

Another alternative is pindolol, another non-selective beta blocker,which can enhance the effects of co-administered antidepressants and hassome 5-HT antagonist property. Pindolol reduced symptoms of performanceanxiety in musicians [44].

Another alternative is nebivolol, a third-generation beta blocker. Inview of its high degree of beta-1 selectivity, its reduced effect on theairways makes it appealing for patients with chronic obstructivepulmonary disease (COPD) and asthma [45, 46]. Thus, either nebivolol oratenolol might be preferred over the nonselective beta blockers forpatients affected by asthma or COPD [47].

Another alternative is betaxolol. Swartz (U.S. Pat. No. 5,798,393)discloses daily oral betaxalol in the treatment of Generalized AnxietyDisorder, PD, and other anxiety-related conditions, stating that“Betaxalol works in 1 to 3 days . . . ” This anxiolytic benefit isprophylactic, as the effects are observed in days, rather than inminutes or hours.

In addition to the already known beta blockers, one can envision amedicinal chemistry approach to develop a structure-activityrelationship (SAR) series of cardio-selective compounds (analogs orderivatives) related to beta blockers and/or their active metabolites invivo, which could be beneficial APIs for compositions of the presentinvention.

Although the FDA-approved beta blockers are synthetic chemicals, anatural product extract of Eucommia bark and leaves has also been shownto have beta adrenergic receptor antagonist properties [48]. The activeingredients of this Asian herbal extract have not been characterized.This material provides another distinct advantage to the presentinvention; an over-the-counter (OTC) anxiolytic pharmaceuticalcomposition for acute anxiety or panic could be produced that containsthe natural product extract of Eucommia in combination with an OTCantiemetic muscarinic receptor antagonist. Depending on the choice ofcountry, suitable and available OTC antiemetic antimuscarinic agentsinclude diphenhydramine, orphenadrine, doxylamine, meclizine, buclizine,cyclizine, and scopolamine. Thus, dual drug combinations could be usedas OTC drug products in certain international markets.

In view of the clinical studies and off-label use of beta blockers,most, if not all psychiatrists are aware that beta blockers can providesome symptomatic relief with regard to performance anxiety [49].However, many psychiatrists are aware that beta blockers alone do notsufficiently address the aggregate symptoms of panic and acute anxiety,and especially the psychic symptoms thereof (e.g., fear, avoidance, andmental anxiety). Thus, there is a need to couple a beta blocker withanother type of active ingredient. This is an essential aspect of thepresent invention.

Scopolamine (or a pharmaceutically acceptable salt thereof) is aplant-derived natural product that is commonly used for the treatment ofmotion sickness, nausea, and vomiting. The mechanism of action of thisantiemetic drug is as an antagonist of muscarinic acetylcholinereceptors. It is a nonselective muscarinic receptor inhibitor that caninhibit all five human receptor subtypes with ˜0.34-5.3 nM Ki values[50]. It is lipophilic and crosses the blood-brain barrier to exertpsychic (CNS) pharmacologic effects. Scopolamine (or salt derivatives)is sold by prescription in the USA as a transdermal patch (TRANSDERMSCOP®)) [51]. However, scopolamine is available without a prescriptionin many foreign markets, where it can be purchased over-the-counter(OTC) or “behind-the-counter” with pharmacist's assistance. Forinstance, in Australia it is an oral OTC product with a recommendedadult dose of 0.3 or 0.6 mg, and a maximum daily dose of 1.2 mg [52].Scopolamine can also be absorbed mucosally, as demonstrated bysublingual delivery [53, 54].

Scopolamine can also exhibit an antidepressant effect when administeredintramuscularly [55], intravenously [56-58] (also disclosed in PCTInternational Publication No. WO 2006/127418), or orally [59]. Thus,scopolamine can affect at least one mood disorder (i.e., depression),which coincidentally is a co-morbid condition in many persons affectedby panic disorder. Another muscarinic receptor antagonist, orphenadrineand its major metabolite, tofenacine, have also been reported to exhibitan antidepressant effect [60-62]. Although depression per se is not theintended medical indication of the present invention, selectedantimuscarinic agents can display psychic (CNS) pharmacologic effect(s),such as the treatment and/or prophylaxis of depression (e.g., majordepressive disorder, MDD).

Although not common knowledge among physicians at present, there is somehistoric evidence that scopolamine can exert anxiolytic effect(s).Scopolamine was described a century ago to have a “calming effect”(verbatim) when injected hypodermically into patients afflicted byvarious psychiatric disorders at doses of 0.2-1.0 mg, which are stillrelevant human doses to this day [63]. This 1906 publication mentioned,“ . . . the calming effect of the medicament . . . . The action ofscopolamine shows itself rapid in maniacal excitement and in acutehallucinatory delirium. The patients become calm gradually, and fallasleep if the dose is somewhat larger.”

A genetic study of the human M2 muscarinic receptor gene (CHRM2) hasrevealed an association between specific genetic polymorphisms and therisk of depression in major depressive syndrome [64]. Consistent withthese pharmacologic and genetic findings in humans, laboratory studieswith rodent models for antidepressant activity using both pharmacologicand gene knock-out approaches revealed that the antidepressant-likeeffects of scopolamine are mediated via the M1 and/or M2 receptors, butnot the M3, M4, and M5 receptors [50]. Thus, the human M2 (and/or M1)receptor-linked second messenger signaling pathways in the CNS arelikely to affect mood and mood disorders (e.g., depression).

Of relevance to our dual drug approach for acute anxiety and panic, areport disclosed the cardiovascular effects of oral atenolol (50 mg),oral scopolamine HBr (0.3 mg), coincident administration of both drugs,and no treatment in healthy volunteers when exposed to heat within asauna [12]. Coincident administration of the two oral drugs revealedessentially the same cardiovascular effects as the beta blocker atenololalone (i.e., reduced heart rate and blood pressure), and either atbaseline prior to heat exposure or during it. A relevant antiemetic oraldose of scopolamine alone or as an adjunct to atenolol displayedessentially no effect with regard to the cardiovascular symptoms. Thus,the cardiovascular effects were due to atenolol. The potential for anypsychiatric and/or psychic (CNS) effects of scopolamine were notenvisioned or addressed by this study.

In view of these results [12] and given that acute anxiety and panic aredriven physiologically in part by increased epinephrine's effects on thecardiovascular system, it is appropriate to include a beta blocker(e.g., atenolol) to address the cardiovascular symptoms per se.Scopolamine alone would not be anticipated to be of benefit for thecardiovascular symptoms of these psychiatric conditions. Palpitationsresulting from elevated heart rate and/or blood pressure are consideredthe predominant symptom that patients are aware of during panic attacksand acute anxiety episodes. The beta blocker within the combinations ofthe present invention can address this primary (major) symptom.

The combination therapies of the present invention may also be of use inother psychiatric disorders, such as alcohol addiction and/orwithdrawal, drug addiction and/or withdrawal, migraine, headache, andaggression.

The abuse of alcohol, prescription drugs, and illegal drugs (e.g.,opioids/opiates and cocaine) are major mental health care concerns. Therepetitive abuse of these chemicals can produce physiologic dependence,tolerance, and addiction. The symptoms of sudden withdrawal depend uponthe abused substance, the impairment of neurological and neuroendocrinepathways, as well as visceral and peripheral somatic organ impairment.The withdrawal from addictive substances produces an array of acutesymptoms, many of which overlap with the symptoms of panic and acuteanxiety. Delirium tremens (DTs) occurs in some alcoholics upon abruptcessation of drinking. The symptoms of alcohol-related DTs are verysimilar to those of panic attacks, and are in part related to betaadrenergic effects. The DTs can have serious and even life-threateningconsequences. The standards-of-care for DTs are oral benzodiazepines.Withdrawal from opioid and/or opiate addiction is physiologicallydistinct from alcohol withdrawal.

With regard to beta blockers in substance abuse, atenolol has been shownin placebo-controlled trials to be beneficial in alcohol withdrawal[65-67]. Pindolol has been used to treat alcohol withdrawal [68].Timolol had a minimal effect on a subset of symptoms of patientsexperiencing alcohol withdrawal [69]. With regard to beta blockers incocaine abuse, propranolol has been used to treat withdrawal andoverdoses [70, 71]. Note that propranolol has also been shown tosuppress tremors [72], consistent with one of the perceived benefits ofbeta blockers in performance anxiety in musicians (above).

Alcohol dependence has been genetically linked to the human CHRM2 geneencoding the M2 muscarinic receptor (as also demonstrated fordepression). Scopolamine has an M1 receptor preference over M2, but itcan also bind the M2 receptor [50, 64]. Thus, there is a convergencebetween the genetic linkage and the pharmacologic studies, therebyproviding a rationale for the use of scopolamine (or other muscarinicreceptor antagonists) in treating alcohol addiction and/or withdrawal.

The prevalence of migraine in the USA according to the American MigrainePrevalence and Prevention (AMPP) study is 11.7% and probable migraine is4.5%, for a combined total of 16.2% [73]. The rate is higher in femalesthan in males. The dual drug approach of the present invention may beappropriate for the treatment of migraine and severe headacheindications. Migraine is a co-morbid condition in approximatelytwo-thirds of patients suffering from panic disorder [6, 74]. Accordingto Smitherman and coworkers, “The first-line migraine prophylactics arenot indicated for PD, and the selective serotonin re-uptake inhibitorsused to treat PD are not efficacious for migraine; thus, separate agentsare often required to address each condition.”[6] Consistent with thatcomment, according to Marazziti and coworkers, “ . . . the comorbidityof headache with panic disorder renders this condition more severe andpossibly responsive to different treatments compared to panic disorderalone.”[75] These two groups of authors are unaware of a single therapythat affects both migraine and PD. But, it is feasible that acombination of a beta blocker plus a muscarinic receptor antagonist mayprovide therapeutic benefit for both conditions—panic and migraine.

Beta-adrenergic receptor antagonists (e.g., atenolol, propranolol,metoprolol, nebivolol, nadolol) are considered to be effectiveprophylactics for chronic or episodic migraine [76-81]. Although onestudy reported no benefit from propranolol for treatment of acutesymptoms [82], there is some, albeit limited, evidence that betaadrenergic receptor antagonists, especially when delivered mucosally,can also have benefit in the therapy of acute migraine [83, 84].

A patent by Innes (U.S. Pat. No. 4,532,244) suggests thattransdermally-delivered scopolamine in a patch might be a prophylacticfor migraine. However, the unconvincing evidence provided therein wasbased upon a single patient who used a scopolamine patch for 30 days.However, the biomedical literature is silent regarding whetherscopolamine might be of benefit in preventing or treating migraine.Another muscarinic receptor antagonist, buclizine, is an API in an OTCcombination drug (MIGRALEVE®) sold in the United Kingdom for thetreatment of migraine.

The dual drug combination of the present invention may be therapeuticfor migraine or headache, and especially so when delivered rapidly, forinstance mucosally (e.g., sublingually).

In an embodiment, the dual drug approach of the present invention may beeffective as a treatment for aggression. Systemic adrenaline can produceexcited, anxious, and aggressive behavior in some individuals.Propranolol has been shown to have a therapeutic effect with regard toaggressive behavior [85, 86]. Augmentation of a beta blocker with the“calming effect” of scopolamine or another antimuscarinic agent mayprovide an effective medication for reducing aggression. For instance,scopolamine has been shown to reduce aggressive behavior in nonhumanprimates under certain environmental circumstances [87].

The pharmaceutical standard-of-care for PA, PD, anxiety, andanxiety-related disorders by psychiatrists (and some other physicians)involves oral daily maintenance medication, whereas the presentinvention involves administration “as needed” (p.r.n.), and preferablyon an occasional basis.

The pharmaceutical standard-of-care for PA, PD, anxiety, andanxiety-related disorders by psychiatrists (and some other physicians)is intended essentially for the long-term prophylaxis of episodes,whereas the present invention is intended for the short-term treatmentof symptoms of episodes as they occur or immediately prior to ananticipated episode.

The pharmaceutical standard-of-care for PA, PD, anxiety, andanxiety-related disorders by psychiatrists (and some other physicians)includes SSRIs and/or benzodiazepines, none of which is the focus of thepresent invention. The common SSRIs and/or benzodiazepines can exhibitunwanted side effects, not anticipated by the dual drug combinations ofthe present invention.

Although many psychiatrists (and some other physicians) are aware ofoff-label (i.e., not FDA-approved) use of beta blockers as prophylacticsfor performance anxiety (e.g., stage fright during musicalperformances), the pharmaceutical standard-of-care for PA, PD, anxiety,and anxiety-related disorders by these physicians does not routinelyinclude the use of beta blockers. Beta adrenergic receptor antagonistscan provide limited benefit, such as the suppression of tachycardia,palpitations, and increased blood pressure, which are symptoms of panicand acute anxiety. These beta adrenergic receptor antagonist medicationsare typically administered for the treatment of hypertension. Thus, eventhough many psychiatrists are familiar with the off-label use of betablockers for performance anxiety, as stated by Zamorski and Albucher,“Beta blockers, once widely touted as effective antipanic medications,have proven disappointing as monotherapy in subsequentplacebo-controlled trials.” [9]

There is a need to augment the limited benefits of a beta blocker (i.e.,cardiovascular properties) with another type of active ingredient toproduce a superior anti-panic or anti-anxiety therapy for use p.r.n.Furthermore, it would be advantageous for the other agent (i.e.,non-beta blocker) to exert some psychic (CNS) pharmacologic benefit(s).

The pharmaceutical standard-of-care for PA, PD, anxiety, andanxiety-related disorders by psychiatrists (and some other physicians)does not include scopolamine. Prescription or over-the-counter (OTC)antiemetic medications acting as muscarinic receptor antagonists cansuppress nausea, vomiting, sweating, motion sickness, sea sickness,morning sickness in pregnancy, some of which are symptoms of panic oracute anxiety. However, the transdermal patch of scopolamine does notprovide suitable pharmacokinetics for rapid therapy of psychic orsomatic symptoms that are the focus of the present invention[51].Furthermore, some of the antiemetic APIs exhibit coincidentantihistamine properties. Examples of the latter are diphenhydramine andmeclizine.

Thus, in view of the foregoing, it follows that a pharmaceuticalcomposition consisting essentially of a beta adrenergic receptorantagonist and a muscarinic receptor antagonist are not in use bypsychiatrists, other physicians, or other prescribers (e.g.,veterinarians or dentists) for treating PA, PD, anxiety, andanxiety-related disorders in particular, or any psychiatric conditionfor that matter in general. Outside of the present invention, we havefound no evidence in the prior art of this particular type of dual drugcombination therapy in use at present by psychiatrists, otherphysicians, or other prescribers for any therapeutic or prophylacticpsychiatric indication(s) in humans or other mammals. Also, outside ofthe present invention, we have found no evidence in the prior art of apsychiatric therapy consisting essentially of a beta blocker and amuscarinic receptor antagonist agent together within a singlepharmaceutical composition, or alternatively of coincident simultaneousadministration of a pair of compositions, wherein one compositioncontains the beta blocker and the other contains the muscarinic receptorantagonist agent. Furthermore, these conclusions occur even though bothclasses of APIs (beta blockers and antimuscarinics) have been incommercial use for over five decades.

Furthermore, the pharmaceutical standard-of-care for PA, PD, anxiety, oranxiety-related disorders by psychiatrists and other physicians does nottypically involve administration via a mucosal route, whereas thepharmaceutical compositions of the present invention may be delivered bythis route, in addition to the oral route. The mucosal routes areespecially useful and may be preferred in cases when “time is of theessence” in producing a pharmacologic effect and/or when the patient isunwilling or unable to swallow an oral solid or liquid dose form, or tobe injected a parenteral dose form. Thus, mucosal delivery is anadditional distinct benefit to the dual drug compositions of the presentinvention.

A dual drug combination is a well-known regulatory paradigm in the USA.There are ample predicate FDA-approved prescription drugs that containtwo or more APIs. A common example is PERCOCET®, a combination ofoxycodone and acetaminophen. Two additional recently-approved examplesare NUDEXTA®, a combination of dextromethorphan and guinidine, andHARVONI®, a combination of ledipasvir and sofosbuvir. In addition,FDA-approved OTC drugs frequently contain more than one API.

Prior to the present invention there was a need for fast-acting (e.g.,mucosally-delivered) pharmaceutical compositions for immediate p.r.n.treatment of acute symptoms of panic and acute anxiety. The presentinvention provides suitable solutions for this previously unmet medicalneed, and with the additional benefits of the APIs not being addictiveand/or Controlled Substances.

BRIEF SUMMARY OF THE INVENTION

What we therefore believe to be comprised by our invention may besummarized inter alia in the following words.

A method for treating a psychiatric condition or disorder or thesymptoms thereof, comprising administering to a living animal, includinga human, a pharmaceutical composition consisting essentially of atherapeutically effective amount of a combination of at least one betaadrenergic receptor antagonist agent and/or pharmaceutically acceptablesalts thereof, and at least one antiemetic muscarinic receptorantagonist agent and/or pharmaceutically acceptable salts thereof, sucha

method wherein the psychiatric condition or disorders are selected fromthe group consisting of panic attack, panic disorder, agoraphobia,anxiety, generalized anxiety disorder, social anxiety disorder,performance anxiety, alcohol addiction, alcohol withdrawal, drugaddiction, drug withdrawal, migraine, headache, post-traumatic stress,post-traumatic stress disorder, and aggression, such a

method wherein the symptoms of the psychiatric condition or disorder areselected from the group consisting of tachycardia, increased bloodpressure, palpitations, nausea, vomiting, mental anxiety, fear,avoidance, dyspnea, hyperventilation, migraine, headache, sweating,trembling, post-traumatic stress, alcohol dependence, drug dependence,restlessness, irritability, and aggression, such a

method wherein the at least one beta adrenergic receptor antagonistagent is selected from the group consisting of propranolol, atenolol,Eucommia extract, and/or pharmaceutically acceptable salts thereof, andwherein the at least one antiemetic muscarinic receptor antagonist agentis selected from the group consisting of scopolamine, diphenhydramine,meclizine, and/or pharmaceutically acceptable salts thereof, such a

method wherein the at least one beta adrenergic receptor antagonistagent is propranolol or atenolol, and/or pharmaceutically acceptablesalts thereof, in an amount of about 10 to 100 mg/dose for an adult, andwherein the at least one antiemetic muscarinic receptor antagonist agentis scopolamine, and/or pharmaceutically acceptable salts thereof, in anamount of about 0.05 to 1.0 mg/dose for an adult, and wherein the dosesare lower for an adolescent or child, such a

method wherein the pharmaceutical composition, when in liquid orsemi-solid form, comprises at least one penetration-enhancing solventselected from the group consisting of ethanol, glycerol, propyleneglycol, ethoxydiglycol, and dimethylsulfoxide or, when in solid form,comprises at least one additional component selected from the groupconsisting of mannitol, a monosaccharide, a disaccharide, a bicarbonatebuffer, a phosphate buffer, a binding agent, and a preservative, such a

method wherein the pharmaceutical composition is in a form selected fromthe group consisting of a spray, an elixir, a solution, a suspension, anemulsion, a gel, a cream, a gum, a powder, a tablet, a capsule, atroche, a suppository, a pill, and a film, and wherein thepharmaceutical composition is administered to the animal, including ahuman, by a route of delivery selected from the group consisting ofmucosal, sublingual, buccal, rectal, vaginal, nasal, parenteral, oral,and topical routes, such a

method wherein the at least one beta adrenergic receptor antagonistagent is propranolol, atenolol, pindolol, nadolol, or nebivolol and/orpharmaceutically acceptable salts thereof, in an amount of about 10 to100 mg/dose for an adult, and wherein the at least one antiemeticmuscarinic receptor antagonist agent is scopolamine, and/orpharmaceutically acceptable salts thereof, in an amount of about 0.05 to1.0 mg/dose for an adult, and wherein the doses are lower for anadolescent or child, and wherein the pharmaceutical composition isadministered to the patient by a route of delivery selected from thegroup consisting of mucosal, sublingual, buccal, rectal, vaginal, nasal,parenteral, and oral routes, such a

method wherein the pharmaceutical composition is administered pro renata (p.r.n.) to the animal, including a human, by a route of deliveryselected from the group consisting of mucosal, sublingual, buccal,rectal, vaginal, nasal, and parenteral routes for rapid therapeuticeffect commencing within 30 minutes or less, or by the oral route ofdelivery, such a

method wherein the at least one beta adrenergic receptor antagonistagent exerts therapeutic effects on somatic cardiovascular symptoms ofthe psychiatric condition or disorder, and the at least one antiemeticmuscarinic receptor antagonist agent exerts therapeutic effects onsomatic non-cardiovascular symptoms and/or central nervous systemsymptoms of the psychiatric condition or disorder, such a

method wherein the pharmaceutical composition when administered to theliving animal, including a human, exerts dryness of the mouth as a sideeffect of the muscarinic receptor antagonist agent, and wherein thisside effect deters continuous or daily administration of thepharmaceutical composition in a human, such a

method for treating a psychiatric condition or disorder or the symptomsthereof in a living animal, including a human, comprising administeringto the patient anticipating symptoms of the psychiatric disorder and/orat the time of a trigger circumstance for the psychiatric disorder orcondition, a pharmaceutical composition consisting essentially of atleast one beta adrenergic receptor antagonist agent and/orpharmaceutically acceptable salts thereof, and at least one antiemeticmuscarinic receptor antagonist agent and/or pharmaceutically acceptablesalts thereof, in a therapeutically effective amount to stop or reducethe symptoms of the psychiatric disorder or condition, together with oneor more pharmaceutically acceptable excipients, such a

method wherein the at least one beta adrenergic receptor antagonistagent is selected from the group consisting of propranolol, atenolol,Eucommia extract, and/or pharmaceutically acceptable salts thereof, andwherein the at least one antiemetic muscarinic receptor antagonist agentis selected from the group consisting of scopolamine, diphenhydramine,meclizine, and/or pharmaceutically acceptable salts thereof, such a

method wherein the at least one beta adrenergic receptor antagonistagent is selected from the group consisting of propranolol, atenolol,pindolol, nadolol, nebivolol, and/or pharmaceutically acceptable saltsthereof and wherein the at least one antiemetic muscarinic receptorantagonist agent is scopolamine and/or pharmaceutically acceptable saltsthereof, such a

method wherein the at least one beta adrenergic receptor antagonistagent is propranolol or atenolol, and/or pharmaceutically acceptablesalts thereof, in an amount of about 10 to 100 mg/dose for an adult, andwherein the at least one antiemetic muscarinic receptor antagonist agentis scopolamine, and/or pharmaceutically acceptable salts thereof, in anamount of about 0.05 to 1.0 mg/dose for an adult, and wherein the dosesare lower for an adolescent or child, such a

method wherein the pharmaceutical composition is administered pro renata (p.r.n.) to the living animal, including a human, by a route ofdelivery selected from the group consisting of mucosal, sublingual,buccal, rectal, vaginal, nasal, and parenteral routes for rapidtherapeutic effect commencing within 30 minutes or less, or by the oralroute of delivery, such a

method for treating a psychiatric disorder or condition or the symptomsthereof in a living animal, including a human, comprising concomitantlyadministering to the patient anticipating symptoms of the psychiatricdisorder and/or at the time of a trigger event for symptoms of thepsychiatric disorder or condition, a pharmaceutical compositionconsisting essentially of at least one beta adrenergic receptorantagonist agent and/or pharmaceutically acceptable salts thereof, and apharmaceutical composition consisting essentially of at least oneantiemetic muscarinic receptor antagonist agent and/or pharmaceuticallyacceptable salts thereof, in therapeutically effective amounts to stopor reduce the symptoms of the psychiatric disorder, such a

method wherein the at least one beta adrenergic receptor antagonistagent is selected from the group consisting of propranolol, atenolol,Eucommia extract, and/or pharmaceutically acceptable salts thereof andwherein the at least one antiemetic muscarinic receptor antagonist agentis selected from the group consisting of scopolamine, diphenhydramine,meclizine, and/or pharmaceutically acceptable salts thereof, such a

method wherein the at least one beta adrenergic receptor antagonistagent is selected from the group consisting of propranolol, atenolol,pindolol, nadolol, nebivolol, and/or pharmaceutically acceptable saltsthereof and wherein the at least one antiemetic muscarinic receptorantagonist agent is scopolamine and/or pharmaceutically acceptable saltsthereof, such a

method wherein the at least one beta adrenergic receptor antagonistagent is propranolol or atenolol, and/or pharmaceutically acceptablesalts thereof, in an amount of about 10 to 100 mg/dose for an adult, andwherein the at least one antiemetic muscarinic receptor antagonist agentis scopolamine, and/or pharmaceutically acceptable salts thereof, in anamount of about 0.05 to 1.0 mg/dose for an adult, and wherein the dosesare lower for an adolescent or child, such a

pharmaceutical composition consisting essentially of a combination of atleast one beta adrenergic receptor antagonist agent and/orpharmaceutically acceptable salts thereof, and at least one antiemeticmuscarinic receptor antagonist agent and/or pharmaceutically acceptablesalts thereof, together with one or more pharmaceutically acceptableexcipients and, when in a liquid or semi-solid form, comprises at leastone penetration-enhancing solvent selected from the group consisting ofethanol, glycerol, propylene glycol, ethoxydiglycol, anddimethylsulfoxide, or when in a solid form comprises at least oneadditional component selected from the group consisting of mannitol, amonosaccharide, a disaccharide, a bicarbonate buffer, a phosphatebuffer, a binding agent, and a preservative, such a

pharmaceutical composition, wherein the at least one beta adrenergicreceptor antagonist agent is selected from the group consisting ofpropranolol, atenolol, alprenolol, acebutolol, betaxolol, bisoprolol,bucindolol, celiprolol, nadolol, sotalol, esmolol, carteolol,carvedilol, mepindolol, nebivolol, oxprenolol, penbutolol, pindolol,landiolol, metoprolol, timolol, labetolol, Eucommia extract, and/orpharmaceutically acceptable salts thereof, such a

pharmaceutical composition, wherein the at least one antiemeticmuscarinic receptor antagonist agent is selected from the groupconsisting of scopolamine, diphenhydramine, meclizine, buclizine,cyclizine, hydroxyzine, pirenzepine, benztropine (benzatropine),atropine, hyoscyamine, butylscopolamine, methylscopolamine, doxylamine,promethazine, trihexyphenidyl, orphenadrine, and/or pharmaceuticallyacceptable salts thereof, such a

pharmaceutical composition, wherein the at least one beta adrenergicreceptor antagonist agent is selected from the group consisting ofpropranolol, atenolol, Eucommia extract, and/or pharmaceuticallyacceptable salts thereof and wherein the at least one antiemeticmuscarinic receptor antagonist agent is selected from the groupconsisting of scopolamine, diphenhydramine, meclizine, and/orpharmaceutically acceptable salts thereof, such a

pharmaceutical composition, wherein the at least one beta adrenergicreceptor antagonist agent is selected from the group consisting ofpropranolol, atenolol, pindolol, nadolol, nebivolol, and/orpharmaceutically acceptable salts thereof and the at least oneantiemetic muscarinic receptor antagonist agent is scopolamine and/orpharmaceutically acceptable salts thereof, such a

pharmaceutical composition which is in a form selected from the groupconsisting of a spray, an elixir, a solution, a suspension, an emulsion,a gel, a cream, a gum, a powder, a tablet, a capsule, a troche, asuppository, a pill, and a film.

DETAILED DESCRIPTION OF THE INVENTION

In spite of the availability of many oral psychiatric pharmaceuticals(e.g., SSRIs and benzodiazepines), there is an unmet need for afast-acting therapy for the p.r.n. treatment of symptoms of episodes ofpanic and acute anxiety. The present invention is focused primarilytoward p.r.n. treatments of the symptoms of panic and anxiety, andpreferably with rapid benefits. In an embodiment, the same or similartreatments may also have benefit with regard to selected otherpsychiatric disorders, such as alcohol addiction and/or withdrawal, drugaddiction and/or withdrawal, migraine, headache, and aggression. Thepresent invention addresses multiple aspects of this unmet medical needvia the following beneficial features, among others.

Affecting Multiple Molecular Targets: The API combinations of theinvention (e.g., propranolol and scopolamine) provide complementarypharmacologic benefits by interaction of the APIs with two or moredissimilar molecular targets. The biochemical pathways of the betaadrenergic and muscarinic receptor gene families are appropriatetargets, as they are involved in some of the symptoms of PA, PD,generalized anxiety disorder, social anxiety disorder, and PTSD. Thosemolecular targets can be components of the central nervous system (CNS),the peripheral nervous system, and/or of somatic tissues (e.g.,cardiovascular and gastrointestinal tissues). The appropriatecombination of APIs affects more molecular targets than could beachieved by using a single API alone (e.g., an oral benzodiazepine). Anantagonist of one class of receptors (e.g., muscarinic) can suppress oneor more symptoms of PA. Whereas, an antagonist of the other class ofreceptors (e.g., beta adrenergic) can suppress other symptoms of PA.This could produce additive and/or synergistic effects of direct benefitto a patient afflicted by PA or anxiety. The invention is conceived tosuppress multiple symptoms of panic and anxiety that are under theregulation of dissimilar biochemical pathways.

Stopping Symptoms or Reducing the Severity of Symptoms: The presentinvention stops or reduces (i.e., minimize the number or severity of)symptoms associated with panic- and anxiety-related disorders, such astachycardia, increased blood pressure (especially systolic),palpitations, nausea, vomiting, mental anxiety, fear, avoidance,trembling (tremors), aberrant breathing (dyspnea and hyperventilation),sweating, migraine, headache, post-traumatic stress, and aggression.

Adverse And Beneficial Side Effects: The APIs of the present inventionhave desirable historic performance characteristics in humans. Forexample, APIs can be selected that are non-addicting and/or eithernon-sedating or minimally sedating. Sedation and lethargy are oftenproblems for many oral daily anxiolytic therapies. Beta blockers arenon-addicting and non-sedating. The antimuscarinic APIs arenon-addicting, and can be non-sedating or minimally sedating atantiemetic doses. Furthermore, both classes of these APIs have beendemonstrated to be well tolerated with minimal side effects during atleast five decades of human use. Dryness of the mouth is a side effectof antiemetic antimuscarinic agents, which provides a benefit. Dry mouthmay discourage the daily or persistent use of the dual drug combinationtherapies, thus reducing any potential for abuse.

Ease of Use: Given the episodic nature of panic and acute anxiety, it isbeneficial to have a suitable pharmaceutical composition of the presentinvention available to a patient known to have manifested panic oranxiety disorder symptoms in the past. The pharmaceutical formulationcould be in a purse, a pocket, a home, a workplace, yet could beimmediately available for use “as needed” (p.r.n.) on occasion. At thetime a patient encountered or anticipated an episode (e.g., a “trigger”circumstance was likely to occur) the combination therapy of the presentinvention can be administered mucosally (or orally) to stop or reduce(i.e., minimize the number or severity of) the symptoms of panic oracute anxiety. The ease of use of these compositions may minimizehospitalization, as in the case of acute psychiatric manifestationsand/or substance abuse.

Replacement or Reduction in Use of Daily Oral Anxiolytic Medications:The present invention can replace or reduce the need for dailymaintenance oral anxiolytic medications (e.g., SSRIs or benzodiazepines)that are used as “prophylactic” drugs. In many cases the latter are usedcontinuously for months, years, or decades. Replacement or reduction ofdaily oral anxiolytic medications with the episodic therapy of thepresent invention could reduce a patient's risk of addiction,dependence, sedation, lethargy, drug tolerance, and toxic exposure tothe conventional psychiatric medications. Furthermore, replacement of a“Controlled Substance” (i.e., benzodiazepine) with effective andnon-addicting APIs is advantageous.

Rapid Drug Delivery by the Mucosal Route: The mucosal route of deliveryprovides for rapid penetration through the mucosa, followed by uptakeinto the circulatory system, resulting in systemic bioavailabilitywithout first-pass hepatic metabolism. Rapid drug delivery is feasiblefor mucosal routes, such as the sublingual, buccal, nasal, vaginal, orrectal routes. The speed at which one would expect a therapeutic benefitby a mucosal route would be second only to the intravenous (parenteral)route of administration. Oral or transdermal delivery is expected to beslower than the mucosal route, by minutes if not hours. Thus, in generalthe relative rates of absorption and therapeutic effect would be:intravenous>mucosal>oral>transdermal. Of these options, mucosal deliveryis “optimal” and preferred in “time is of the essence” therapy, becauseit is convenient to administer and does not involve theself-administration by injection with needles.

It is normative for psychiatrists (and some other physicians) to treatpatients afflicted with PA, PD, anxiety, and anxiety-related disorderswith daily oral psychiatric medications. The intention is “maintenance”prophylaxis to block or suppress the onset of panic or anxiety. Bycomparison, the present invention provides a new paradigm forpharmaceutical therapy to be prescribed by physicians for patientshaving panic or anxiety. This new concept is not a persistent daily oralmedication to replace a patient's routine daily benzodiazepine and/orSSRI medication; it is fundamentally different. The present invention isan episodic therapy for the symptoms of panic or anxiety, per se, and isto be taken “as needed” at the discretion of the patient. The patientwho suffers only occasionally a PA event shall take the pharmaceuticalcomposition of the present invention only occasionally. For instance, ifa patient experienced only one panic or heightened anxiety event perweek, then the medication of the present invention would be appropriateonly at that time of the event or immediately preceding it (inanticipation of an event). Thus, therapy would be self-administered by apatient on only one day that week.

Another way of describing this is the difference between “chronic”maintenance medication vs. “acute” p.r.n. therapy for the symptoms of anepisode. In this descriptive context, the normal practice of psychiatryis oral benzodiazepines or SSRIs as “chronic” maintenance medications.However, the new paradigm is “acute” p.r.n. therapy of symptoms by useof the compositions of the present invention. Unlike the abundance ofchoices of prophylactic medicines, there are presently no “fast-acting”drugs for the p.r.n. treatment of the acute symptoms of a panic attackper se at the time of an event or in immediate anticipation of an event.

The present invention may affect the somatic (e.g., peripheral andvisceral) symptoms as well as the psychic (CNS) symptoms of panic- andanxiety-related disorders. The pharmaceutical compositions of thepresent invention were designed in view of an optimal treatment of theaggregate symptoms of panic attacks. The combination therapies may alsobe of benefit to patients manifesting somatic and/or psychic symptoms ofanxiety and anxiety disorders, such as generalized anxiety disorder,social anxiety disorder (social phobia), performance anxiety (e.g.,stage fright), agoraphobia, post-traumatic stress and PTSD. Furthermore,the combination therapies may also be beneficial in treating alcoholaddiction and/or withdrawal (alcohol withdrawal syndrome), drugaddiction and/or withdrawal (e.g., opioids, opiates), migraine,headache, and aggression.

The pharmaceutical compositions of the present invention consistessentially of an antiemetic muscarinic receptor antagonist drug and abeta adrenergic receptor antagonist drug, wherein the antiemeticmuscarinic receptor antagonist drug and/or beta adrenergic receptorantagonist drug may be in the form of a free base or a pharmaceuticallyacceptable salt thereof.

The phrase “pharmaceutically acceptable”, as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not typically produce untoward reactions when administered to amammal (e.g., human). Preferably, as used herein, the term“pharmaceutically acceptable” means approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopeia(USP), National Formulary (NF), or other generally recognizedpharmacopeia for use in mammals, and more particularly in humans. APIsof the present invention may be in the form of pharmaceuticallyacceptable salts. “Pharmaceutically acceptable salts” refers to thosesalts which possess the biological effectiveness and properties of theparent compound and which are not biologically or otherwise undesirable.

The pharmaceutical compositions of the present invention consistessentially of a beta adrenergic receptor antagonist drug and anantiemetic muscarinic receptor antagonist drug. One of the combinationtherapies of interest within the present invention is a beta blocker(e.g., propranolol or atenolol) plus scopolamine. The combination of abeta blocker and an antimuscarinic agent has not been used clinicallyfor panic or anxiety indications, or for that matter any psychiatricmedical indication, outside of the present invention.

The pharmaceutical compositions of the present invention may include,specifically, propranolol or atenolol (or other beta blockers) incombination with scopolamine (or other muscarinic receptor antagonistagents), or the salts, pro-drugs, or analogs, derivatives, ormetabolites thereof.

With regard to the pharmaceutically acceptable salts, propranolol HClhas been delivered sublingually at 10 and 40 mg per dose in adults [13,14]. Propranolol in INDERAL® is available in oral doses ranging from 10to 80 mg per dose for the treatment of hypertension. Depending on theindication multiple doses per day are permitted. The present inventionprovides a target dose in the range of about 10-100 mg per dose ofpropranolol in adults. It may be preferable to use a target dose ofabout 20-80 mg per adult, which are conventional dosages for treatinghypertension. It might be even more preferable to use a target dose ofabout 20-40 mg per adult, especially for mucosal delivery. The dose foradolescents and children would be less than an adult's dose.

Atenolol is available in oral doses ranging from 25 to 100 mg per dosefor the treatment of hypertension. Depending on the indication multipledoses per day are permitted. The present invention provides a targetdose in the range of about 10-100 mg per dose of atenolol in adults. Itmight be more preferable to use a target dose of about 20-80 mg peradult. It might be even more preferable to use a target dose of about20-50 mg per adult, especially for mucosal delivery. The dose foradolescents and children would be less than an adult's dose.

The pharmaceutical composition of the present invention comprises a betaadrenergic receptor antagonist agent selected from the group consistingof propranolol, atenolol, alprenolol, acebutolol, betaxolol, bisoprolol,bucindolol, celiprolol, nadolol, sotalol, esmolol, carteolol,carvedilol, mepindolol, nebivolol, oxprenolol, penbutolol, pindolol,landiolol, metoprolol, timolol, labetolol, and Eucommia extract, whereinthe beta adrenergic receptor antagonist agent may be in the form of afree base or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition of the present invention comprises anantiemetic muscarinic receptor antagonist agent selected from the groupconsisting of scopolamine, diphenhydramine, meclizine, buclizine,cyclizine, hydroxyzine, pirenzepine, benztropine (benzatropine),atropine, hyoscyamine, butylscopolamine, methylscopolamine, doxylamine,promethazine, trihexyphenidyl, and orphenadrine (or its metabolite,tofenacine), wherein the antiemetic muscarinic receptor antagonist agentmay be in the form of a free base or a pharmaceutically acceptable saltthereof.

With regard to the pharmaceutically acceptable salts, scopolamine HBrhas been delivered sublingually at 0.15 mg/dose in adults [53], orallyat 0.4-1.0 mg/dose in adults [54, 59], and transdermally(TRANSDERMSCOP®) at 1.5 mg/dose/3 days in adults for the treatment ofmotion sickness, sea sickness, nausea and vomiting. The presentinvention provides a target dose range of about 0.05-1.0 mg ofscopolamine in adults. It might be preferable to use a target dose of0.2-0.6 mg per adult for oral delivery, and 0.05-0.3 mg per adult formucosal delivery. For comparison, in Australia scopolamine is an OTCoral product with a recommended adult dose of 0.3 or 0.6 mg, and amaximum daily dose of 1.2 mg [52]. The dose for adolescents and childrenwould be less than an adult's dose.

Closely-related derivatives of scopolamine are alternativeantimuscarinic APIs, such as butylscopolamine, methylscopolamine,atropine, hyoscyamine (the levo isomer of atropine), and benztropine(benzatropine). For instance, peripherally-acting butylscopolamine(scopolamine butylbromide) is used for the treatment of abdominalspasms. The butylbromide modification prevents the API from crossing theblood-brain barrier. However, direct pharmacologic action by theantiemetic upon the CNS is preferable, if not necessary, for the presentinvention in mediating psychic benefits. Thus, in an embodiment,central-acting lipophilic antimuscarinic agents (e.g., scopolamine) arepreferred, especially with regard to psychic symptoms (e.g., fear,avoidance, and mental anxiety). In addition, one can envision amedicinal chemistry approach to develop novel structure-activityrelationship (SAR) series of CNS-active compounds related to scopolamineor other muscarinic inhibitors, which could be beneficial APIs forcompositions of the present invention.

In addition to the scopolamine family of APIs, other closely-relatedfamilies of APIs exhibiting antimuscarinic activities are included inthe present invention. In some cases the APIs also exhibit antihistamineproperties. Examples of other antiemetic antimuscarinic agents include:(a) diphenhydramine (BENADRYL®), orphenadrine (an OTC in Canada) and itsmetabolite tofenacine, and doxylamine (UNISOM® or NYQUIL®), all basedupon an ethanolamine moiety; and (b) meclizine (DRAMAMINE® Less DrowsyFormulation or BONINE®), buclizine, cyclizine, hydroxyzine (ATARAX®),and pirenzepine, all based upon a piperazine moiety. Hydroxyzine issometimes prescribed for anxiety [88] and might be beneficial intreating panic disorder [89]. As stated above, CNS accessibility by themuscarinic receptor antagonist is preferable. Pirenzepine is M1selective, but it lacks CNS effects, and is thus less likely to producesome of the advantageous properties of this class of antagonists.Furthermore, other types of antiemetic antimuscarinic agents areavailable, such as promethazine and trihexyphenidyl.

The pharmaceutical compositions of the present invention may compriseone or more excipients. Excipients which may be used include carriers,surface active agents (surfactants), thickening (viscosity) agents,emulsifying agents, binding agents, dispersion or suspension agents,buffering agents, penetration-enhancing agents, solubilizers, colorants,sweeteners, flavoring agents, coatings, disintegrating agents,lubricants, preservatives, isotonic agents, and combinations thereof.The selection and use of suitable excipients is taught in Gennaro, ed.,Remington: The Science and Practice of Pharmacy, 20th Ed. (LippincottWilliams & Wilkins 2003), the disclosure of which is incorporated hereinby reference.

The term “carrier” applied to pharmaceutical compositions of theinvention refers to a diluent, excipient, or vehicle with which anactive compound is administered. Such pharmaceutical carriers can beliquids, such as water, saline solutions, aqueous dextrose solutions,aqueous glycerol solutions, and lipids and oils, including those ofpetroleum, animal, vegetable or synthetic origin. Suitablepharmaceutical carriers are described in “Remington's PharmaceuticalSciences” by E. W. Martin, 18^(th) Edition.

The pharmaceutical compositions of the present invention consistingessentially of beta adrenergic receptor antagonists and muscarinicreceptor antagonists may be in the form of a solid, a semi-solid, or aliquid dose form. Examples include sprays, elixirs, solutions,suspensions, emulsions, gels, creams, gums, powders, tablets, capsules,troches, suppositories, pills, and films. A variety of mechanicaldevices may be used to dispense the formulations, for instance pumpapplicators, spray applicators, and compressible tube dispensers. Thedevices may deliver calibrated unit doses, for instance in the cases ofliquid or semi-solid dosage forms.

The pharmaceutical compositions of the present invention, when intendedfor sublingual, buccal, and/or oral delivery, may benefit fromtaste-masking with natural and/or artificial flavors and/or sweeteners(e.g., mannitol, monosaccharides, and disaccharides). Mouth paresthesia(numbness) can occur with propranolol HCl as a perceived adverse effect[14]. Paresthesia and an undesirable taste were observed for sublingualdose forms containing propranolol during development of the presentinvention. However, neither property was observed for atenolol insublingual dose forms, thus providing two distinct advantages for thisparticular beta blocker.

In addition, using methods known to those skilled in the art, analogsand derivatives of the APIs of the invention can be created which haveimproved therapeutic efficacy in controlling panic and anxiety, i.e.,higher potency and/or selectivity at a specific targeted receptor type,either greater or lower ability to penetrate mammalian blood-brainbarriers, fewer side effects, etc.

The term “analog” or “derivative” or “metabolite” is used herein in theconventional pharmaceutical sense, to refer to a molecule thatstructurally resembles a reference molecule, but has been modified in atargeted and controlled manner to replace one or more specificsubstituents of the reference molecule with an alternate substituent,thereby generating a molecule which is structurally similar to thereference molecule. Synthesis and screening of analogs (e.g., usingstructural and/or biochemical analysis), to identify slightly modifiedversions of a known compound which may have improved or biased traits(such as higher potency and/or selectivity at a specific targetedreceptor type, greater ability to penetrate mammalian blood-brainbarriers, fewer side effects, etc.) is a drug design approach that iswell known in pharmaceutical chemistry.

The pharmaceutical compositions of the present invention may includebiocompatible buffering agents, such as sodium bicarbonate (pKa 6.4),sodium phosphate buffer (mono- and di-basic admixtures; pKa 6.8), orcitric acid. For instance, in the event of sublingual or buccal deliverybuffering to approximate the pH of saliva (pH 6.2-7.4) might beadvantageous. In certain instances the chemical stability of one or moreof the APIs within the formulation might benefit from the inclusion ofbiocompatible buffering agents. In certain conditions the physicalstability of the liquid and/or semi-solid formulations might benefitfrom the inclusion of biocompatible buffering agents. Bicarbonates andphosphates are considered as physiologic buffers in mammals and humans.In certain compositions it might be preferable to maintain an acidic pHor acidic-to-neutral pH to prevent decomposition of an API (e.g.,propranolol).

The pharmaceutical compositions of the present invention may includechemical preservatives, in addition to ethanol and/or glycerol in liquidand semi-solid compositions. Ethanol and glycerol are known to exhibitantibacterial properties. Examples of commonly used preservativesinclude sodium benzoate, benzyl alcohol, methyl paraben, propyl paraben,and butyl paraben, among others.

The pharmaceutical compositions of the present invention, when in liquidor semi-solid forms, may include one or more penetration-enhancingsolvents such as ethanol, glycerol, propylene glycol, and/orethoxydiglycol. In some circumstances, dimethylsulfoxide (DMSO) may beincluded as a skin penetration enhancer. However, DMSO may yield anunpleasant garlic flavor, even when applied to sites remote from theoral cavity.

Compositions of the present invention can also be formulated for vaginalor rectal administration, such as suppositories, films, viscous gels,creams, or retention enemas (e.g., containing conventional suppositorybases such as cocoa butter or other glycerides).

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient(s). The pack may, for example, comprise metal orplastic foil, such as a blister pack. Compositions of the inventionformulated in a compatible pharmaceutical carrier may also be prepared,placed in an appropriate container, and labeled for treatment of anindicated condition.

The pharmaceutical compositions of the present invention may includesurfactants, such as phospholipids (e.g., lecithin) and sodium laurylsulfate. Surfactants help solubilize otherwise insoluble APIs oringredients. Surfactants might be needed in certain drug combinationcompositions to produce emulsions or suspensions.

The pharmaceutical compositions of the present invention may includehydrophobic components, such as lipids, oils (e.g., isopropyl myristateand isopropyl palmitate), fatty acids, unsaturated fatty acids, waxes,petrolatum, lanolin, etc.

The pharmaceutical compositions of the present invention may includemanufactured admixture “bases” typically used in extemporaneouscompounding of pharmaceutical products. These “bases” are commerciallyavailable to pharmacists working in compounding pharmacies. Vendors ofadmixture “bases” include PCCA, Medisca, Letco, Paddock Laboratories,and Transderma, among others. In this context, the term “base” does notrefer to alkalinity or pH. Rather they are “bases” into which activeand/or inactive ingredients are mixed. The “bases” can be intended forspecific routes of delivery, such as elixirs, syrups, and sweetenedsyrups for oral and oral mucosal delivery.

For administration in liquid or semi-solid forms, the APIs can becombined with pharmaceutically acceptable carriers (e.g., ethanol,glycerol, water), suspending agents (e.g., sorbitol syrup), emulsifyingagents (e.g., lecithin), viscosity agents (e.g., methyl cellulose,polyethylene glycols, or Carbomer Homopolymer Type A), non-aqueousvehicles (e.g., a plant-derived oil), preservatives (e.g., a paraben),and the like. Stabilizing agents such as antioxidants (e.g., citricacid) can also be added.

For administration in the form of a tablet (sublingual or oral) orcapsule (oral), the APIs can be combined with pharmaceuticallyacceptable excipients, such as binding agents (e.g., starch); fillers(e.g., mannitol); lubricants (e.g., magnesium stearate); dispersants ordisintegrants (e.g., starch); or wetting agents (e.g., sodium laurylsulphate), coloring and flavoring agents, gelatin, sweeteners (e.g.,mono- or di-saccharides), natural and synthetic gums (e.g., acacia),buffer salts (e.g., sodium bicarbonate), waxes, and the like.

The tablets can be coated by methods well known in the art. Thecompositions of the invention can be also introduced in microspheres,e.g., fabricated from polyglycolic acid/lactic acid (PGLA). Liquidpreparations for oral administration can take the form of, for example,solutions, syrups, emulsions or suspensions, or they can be presented asa dry product (e.g., powder) for reconstitution with water or othersuitable vehicle before use. Preparations for oral administration can besuitably formulated to give controlled or postponed release of theactive compound. Controlled or postponed release may apply to one ormore of the APIs within the composition, and may also apply to portionsof one or more of the APIs within the composition. The APIs can also beadministered in the form of liposome delivery systems. Liposomes can beformed from a variety of lipids and phospholipids, such as cholesterol,stearylamine or phosphatidylcholines, as is well known.

For administration by nasal inhalation, the therapeutics according tothe present invention can be conveniently delivered in the form of anaerosol spray presentation from pressurized packs or a nebulizer, withthe use of a suitable propellant, (e.g., dichlorodifluoromethane). Inthe case of a pressurized aerosol, the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules (e.g., gelatin)and cartridges for use in an inhaler or insufflator can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

The pharmaceutical compositions of the present invention may bedelivered by mucosal or oral routes. A preferred route of delivery forthe present invention is mucosal, as this route avoids GI metabolism andmore significantly first-pass metabolism by the liver. For instance,within the oral mucosal environment at least two routes of absorptionare possible—sublingual and buccal. Mucosal delivery is beneficial andpreferred for p.r.n. administration, as well as to hasten the effects ofthe compositions. Coincidentally, a “chewing” gum (for sublingual,buccal, and/or oral delivery) might have the additional perceivedbenefit as a palliative agent. A patient could chew on it for some timewhile anticipating or waiting for the onset of a pharmacologic benefit.

Outside of the oral cavity, the pharmaceutical compositions of thepresent invention could be delivered to the mucosa of the rectum, thevagina, or nasal passages. These latter routes could be used in certaincircumstances, such as a patient's aversion to the taste of acomposition, or a patient's unwillingness or inability to swallow, orwhile a patient is prone to vomiting.

In addition to various mucosal routes of delivery (with expected rapidbioavailability), another preferred route is oral, essentially forease-of-use by the patient. The oral route (e.g., tablets, capsules, andelixirs) is preferred when a patient anticipates in the future (e.g., inone hour) a “trigger” circumstance that is likely to lead into the onsetof symptoms of panic or anxiety. The patient who expects to encounter atrigger circumstance self-administers the medication p.r.n. orally andwaits a sufficient period of time (e.g., one hour) to enable GIabsorption and bioavailability, prior to encountering the trigger. Inother words, the effect of the oral route is likely to be somewhatdelayed relative to a mucosal route.

In an embodiment, a topical formulation might be preferred, for instanceto provide slower release or sustained-release of the combination ofAPIs. In another embodiment, in certain circumstances a parenteralformulation might be preferred, such as an intravenous injectionintended for very rapid effect (e.g., less than 15 minutes) duringsymptoms of panic or anxiety.

The present invention is administered as a therapy to be taken at thetime of an episode or in anticipation of an episode, rather than as adaily and/or persistent oral product for the prophylactic suppression ofpanic or anxiety. The pharmaceutical compositions of the invention aremade available to the patient in advance of a panic or anxiety episodeor a trigger circumstance thereof. The patient is able to self-medicateat the time of symptoms, or earlier at the time of the trigger, or evenearlier in anticipation of the trigger. For instance, the p.r.n.self-administration of the dual drug combination might occur 10, 20, 30,40, 50, or 60 minutes prior to the anticipated symptoms of panic oracute anxiety. Furthermore, when “time is of the essence” the mucosalroutes of delivery are preferred, especially sublingual dose forms.

In an embodiment, a sublingual or buccal formulation is administered bythe patient at the time of a panic or anxiety episode or in anticipationof a trigger of an episode, thus helping enable the patient to regainsome or full control over their symptoms as needed.

In an embodiment, combination therapies with two (or more) APIs can besold to patients in need of a treatment, albeit subject to variousregulatory oversight processes. For instance within the USA, compoundingpharmacies may formulate multiple APIs into a non-sterile compoundedpharmaceutical product (via the 503A pathway) or into a sterilemanufactured compounded pharmaceutical product (via the 503B pathway),provided that the APIs have been included in at least one FDA-approvedmedication. These compounded products are sold by prescription and aresubject primarily to state boards of pharmacy. Alternatively,combination drug products may be approved for specific medicalindications through the FDA's drug approval processes for sale topatients in need of therapy as either prescription drugs orover-the-counter (OTC) drugs. Thus, the combination therapies of theinvention could be sold as “unapproved” compounded prescription (Rx)medicines, and/or as FDA-approved Rx drugs, and/or as FDA-approved OTCdrugs.

The amount of APIs which can be combined with a carrier material toproduce a single dosage form will vary depending upon the subject beingtreated, and the particular mode of administration, and will generallybe that amount of the composition which produces a therapeutic effect.The dosage amount would be less in adolescents and children than in anadult, and might be a function of body mass or body surface area.

The present invention relates to compositions and methods for treatingan animal, including a human. The subjects being treated with thepresent invention include adults, adolescents and children. The animals,including humans, may be patients under the care of a licensedphysician, physician assistant, dentist, nurse practitioner, orveterinarian.

The present invention is useful in the p.r.n. treatment of non-humananimals, such as under the care of a veterinarian. For instance,domesticated pets (e.g., dogs and cats) can be adversely affected byseparation anxiety, as well as by specific phobic triggers, such asnoises, containment, or treatment by a veterinarian or caretaker. Largedomesticated livestock (e.g., cattle, swine, sheep, and horses) may alsobenefit from the anxiolytic compositions of the present invention. Thedose ranges for the APIs required for therapeutically effectivetreatment of non-human animals can be estimated using allometric scalingfrom the intended human dose range.

The term “therapeutically effective” applied to dose or amount refers tothat quantity of a compound or pharmaceutical composition that issufficient to result in a desired activity upon administration to aliving animal body.

A therapeutically effective amount of a pharmaceutical compositionconsisting essentially of a beta adrenergic receptor antagonist drug andan antiemetic muscarinic receptor antagonist drug, for examplepropranolol or atenolol and scopolamine, results in cessation or adecrease in severity of panic and anxiety symptoms, and/or a preventionor impairment of the onset of panic and anxiety symptoms.

In an embodiment, this invention provides pharmaceutical compositionsconsisting essentially of a beta adrenergic receptor antagonist drug andan antiemetic muscarinic receptor antagonist drug forself-administration by a patient experiencing anxiety, or inanticipation of panic or anxiety, and/or at the time of a trigger eventfor panic or anxiety, in order to stop or minimize the number orseverity of the symptoms of panic or anxiety. The benefit of the dualdrug approach is superior to an antimuscarinic therapy alone or a betablocker therapy alone.

In an embodiment, this invention provides pharmaceutical compositionsconsisting essentially of propranolol or atenolol and scopolamine in atherapeutically effective amount to stop or reduce the symptoms of panicor anxiety.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or and consisting essentially of language.When used in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the invention so claimed areinherently or expressly described and enabled herein.

In an embodiment, this invention provides a method for treating PA, PD,anxiety, or an anxiety disorder in a subject, comprising administeringto a subject anticipating a PA or anxiety and/or at the time of atrigger circumstance for panic or anxiety, a pharmaceutical compositionconsisting essentially of propranolol or atenolol and scopolamine in atherapeutically effective amount to stop or reduce the symptoms of panicor anxiety.

In an embodiment, this invention provides a method for treating PA, PD,anxiety, or an anxiety disorder in a subject, comprising administeringto a subject anticipating a PA or anxiety and/or at the time of atrigger circumstance for panic or anxiety, a pharmaceutical compositionconsisting essentially of a beta adrenergic receptor antagonist drug andan antiemetic muscarinic receptor antagonist drug in a therapeuticallyeffective amount to stop or reduce the symptoms of panic or anxiety.

In a further embodiment, this invention provides a method for treatingPA, PD, anxiety, or an anxiety disorder consisting of administering apharmaceutical composition consisting essentially of a beta adrenergicreceptor antagonist drug and an antiemetic muscarinic receptorantagonist drug in a therapeutically effective amount to stop or reducethe symptoms of anxiety or panic at the onset of anxiety or panic.

In yet another embodiment, this invention provides a method for treatinganxiety, an anxiety-related disorder, PA, or PD in a subject, comprisingconcomitantly administering to the subject experiencing anxiety orpanic, or anticipating anxiety or panic, and/or at the time of a triggerevent for anxiety or panic, a pharmaceutical composition consistingessentially of a beta adrenergic receptor antagonist agent and apharmaceutical composition consisting essentially of an antiemeticmuscarinic receptor antagonist agent in therapeutically effectiveamounts to stop or reduce the symptoms of anxiety or panic.

In another embodiment, a broader group of psychiatric disordersextending beyond panic and anxiety may be treated p.r.n. using dual-drugcompositions or two APIs in separate compositions concomitantly. Theadditional psychiatric disorders include alcohol addiction and/orwithdrawal, drug addiction and/or withdrawal, migraine, headache, andaggression. Thus, in this broader context the symptoms of psychiatricdisorders are selected from the group consisting of tachycardia,increased blood pressure, palpitations, nausea, vomiting, mentalanxiety, fear, dyspnea, hyperventilation, migraine, headache, sweating,trembling (tremors), avoidance, post-traumatic stress, drug dependence,drug addiction, alcohol dependence, alcohol addiction, irritability, andaggression.

In yet another embodiment, a dual drug composition of the presentinvention provides a multiplicity of benefits to the patient afflictedby acute anxiety or panic. The beta blocker provides benefits withregard to cardiovascular symptoms (e.g., palpitations, heart rate, BP);the antimuscarinic agent provides benefits with regard tonon-cardiovascular symptoms (e.g., nausea, vomiting, mental anxiety,avoidance, etc.); and the antimuscarinic agent provides another benefitas the result of it side effect, dry mouth. This latter side effect mayhelp prevent abuse and addiction of the combination therapy intended foroccasional p.r.n. usage. In other words, both the intended positivepharmacologic effects and the dry mouth side effect of theantimuscarinic agent is uniquely suited to a p.r.n. therapy approach,that is not appropriate or less appropriate for a daily oral anxiolyticmedication.

EXAMPLES

The subject matter of the present invention will be better understood inconnection with the following examples, which are intended as anillustration of and not a limitation upon the scope of the invention. Itwill be apparent to those skilled in the art that the described examplesare merely representative in nature.

The active pharmaceutical ingredients of the present invention, togetherwith one or more conventional adjuvants, carriers, or diluents, may beplaced into the form of pharmaceutical compositions and unit dosagesthereof, and in such form may be employed as solids (e.g., coated oruncoated tablets or filled capsules), or liquids or semi-solids (e.g.,solutions, suspensions, emulsions, creams, gels, elixirs, or capsulesfilled with the same), all for oral or mucosal use; in the form ofsuppositories or capsules for rectal and vaginal administration.

Such pharmaceutical compositions and unit dosage forms thereof maycomprise conventional or new ingredients in conventional or specialproportions, with or without additional active compounds or principles,and such unit dosage forms may contain any suitable effective amount ofthe active ingredient commensurate with the intended dosage range to beemployed. Tablets containing twenty (20) to two hundred (200) milligramsof active ingredient(s) or, more broadly, ten (10) to three hundred(300) milligrams of active ingredient(s) per tablet, are accordinglysuitable representative unit dosage forms, as solids. With regard toliquids containing the combination therapeutic agents, such as alcoholicelixirs for oral or sublingual administration, a volume of about onehundred (100) microliters to about five (5) milliliters per unit dose isa suitable representative unit dosage volume. With regard to semi-solidscontaining the combination therapeutic agents, such as gels or creamsfor vaginal or rectal administration, a volume of about one half (0.5)milliliter to about five (5) milliliters is a suitable representativeunit dosage volume. Consideration would also be given to the estimatedmaximum number of consecutive unit doses administered per period oftime, such as per 6, 12, or 24 hours.

Example 1 Liquid Pharmaceutical Compositions

Ingredients: # 1 # 2 # 4 Propranolol HCl 1.2 g 1.2 g 1.2 g ScopolamineHBr, Trihydrate 15 mg 30 mg 15 mg Ethanol, 95% 1.5 ml 3.0 ml 3.0 mlGlycerol 1.5 ml 3.0 ml 3.0 ml Propylene Glycol 3.0 ml 3.0 ml — PurifiedWater QS 15 g QS 15 g QS 15 g

As examples of aqueous liquid pharmaceutical compositions, alcoholicelixirs are prepared consisting of 80 mg/ml propranolol HCl, 1-2 mg/mlscopolamine HBr, 10-20% ethanol, 10-20% glycerol, and 0-20% propyleneglycol. The dose is 0.5 ml of the alcoholic elixir in an adult, with adelivered dose of 40 mg propranolol HCl and 0.5 or 1.0 mg scopolamineHBr. The APIs are soluble in these elixirs at room temperature, but aprecipitate may form at or near freezing when stored for multiple daysin a refrigerator.

The preferred route of delivery for elixir compositions is oral.Taste-masking flavors and sweeteners may be incorporated into thecomposition, because propranolol HCl has an “acidic” and “medicine”taste and it produces mouth paresthesia when placed under or on thetongue. These undesirable properties were noted in humans duringdevelopment of the liquid compositions. Alternative beta blockers may bechosen that lack these undesirable properties, such as atenolol.

The pH of the alcoholic elixirs (samples #1, 2, and 4) is ˜4.5 withoutbuffering. It may be beneficial to include a buffering agent or agents(e.g., bicarbonate or phosphate) to increase and buffer the pH to thatof the oral cavity (˜6.2-7.4) for sublingual or oral delivery. Forinstance, sodium bicarbonate can be included at a ratio (by mass)relative to propranolol HCl of about 1:50 to about 1:20, to increase thepH toward neutrality. For instance a ratio of ˜1:26 of sodiumbicarbonate to propranolol HCl raised the pH of elixir #4 to ˜pH6.5-7.0.

The alcohols (i.e., ethanol, glycerol, and propylene glycol) within theelixir may provide penetration enhancement of the APIs and apreservative property. The elixir can be dispensed by a unit-dosemetered pump or spray applicator (e.g., delivering 0.5 or 0.25 ml foreach pump action).

The alcoholic elixirs (samples #1, 2, and 4) had low viscosities of <10cP when measured using a Brookfield viscometer.

In other liquid compositions, one may substitute other beta blockers inlieu of propranolol HCl and/or other antiemetic muscarinic receptorantagonist agents in lieu of scopolamine HBr.

Example 2 Viscous Liquids & Semi-Solid Pharmaceutical Compositions

Ingredients: # 7 # 8 # 9 # 10 Propranolol HCl 600 mg 600 mg 600 mg 600mg Scopolamine HBr, 15 mg 15 mg 15 mg 15 mg Trihydrate Glycerol — — QS15 g QS 15 g Propylene Glycol 3.0 ml 3.0 ml 3.0 ml 3.0 ml PolyethyleneGlycol (300) — 4.5 ml 4.5 ml 4.5 ml Methyl Cellulose — 300 mg — 300 mg(4000 Mpas) Spira-Wash Gel QS 15 g — — — Sodium Bicarbonate — — — 30 mgPurified Water — QS 15 g — —

As examples of viscous liquid and semi-solid (e.g., gel, cream, oremulsion) pharmaceutical compositions for use in mucosal delivery (e.g.,for rectal or vaginal application), formulations are prepared consistingof 40 mg/ml propranolol HCl and 1 mg/ml scopolamine HBr as the APIs. Theinactive excipients are selected from: (a) alcoholic penetrationenhancers and preservatives—propylene glycol and glycerol; (b) viscosityagents—polyethylene glycol, methyl cellulose, and Spira-Wash Gel™ base(PCCA); and (c) a buffering agent—sodium bicarbonate, for use in therectum or in the vagina in post-menopausal women. Note that Spira-WashGel™ is an extemporaneous compounding base that contains polyethyleneglycols and propylene glycol, among other ingredients. The dosage is 0.5ml in an adult, with a delivered dose of 20 mg propranolol HCl and 0.5mg scopolamine HBr.

The pH of the semi-solid formulations is ˜4.5 without buffering (e.g.,sample #8) and ˜5.0-5.5 with bicarbonate buffering at a ratio of 1:20 ofsodium bicarbonate to propranolol HCl (e.g., sample #10). The vagina ofreproductive-age women is acidic (pH 3.8-4.4), and would not require abuffering agent. A buffering agent or agents (e.g., bicarbonate orphosphate) may be included to increase and buffer the pH toward theneutral pH of the rectum or post-menopausal vagina. A preservative agentmay be included.

The viscosities of samples #9 and #10 were determined using a Brookfieldviscometer at ca. 200-250 cP. The viscosities of samples #8-10 could befurther increased by additional methylcellulose and/or higher molecularweight polyethylene glycol(s). Of the four samples, the most viscous issample #7, containing Spira-Wash Gel (PCCA) as the majority component.

The aqueous semi-solids (or “viscous liquids”) may be dispensed by adisposable single-dose applicator (e.g., delivers 0.5 or 1.0 ml for eachpump action), such as a syringe-like device. Alternatively, semi-solidsuppositories with higher viscosity may be prepared for manual insertioninto the rectum or vagina.

In other viscous liquid or semi-solid compositions, one may substituteother beta blockers in lieu of propranolol HCl and/or other antiemeticmuscarinic receptor antagonist agents in lieu of scopolamine HBr.

Example 3 Solid Pharmaceutical Compositions

Ingredients: # 11 # 13 # 14 # 23 # 25 Propranolol 2.0 g 2.0 g — — — HClAtenolol — — 2.5 g 1.83 g 3.05 g Scopolamine 50 mg 25 mg 25 mg 18 mg 30mg HBr, Trihydrate Mannitol 3.5 g 3.34 g 2.99 g 2.86 g 0.85 g Starch 1.4g 1.4 g 1.4 g 1.2 g 1.0 g Sodium Bi- 50 mg 200 mg 50 mg 60 mg 50 mgcarbonate Magnesium — 35 mg 35 mg 30 mg 25 mg Stearate Total 7.0 g 7.0 g7.0 g 6.0 g 5.0 g

With regard to solid pharmaceutical compositions, powders, tablets, andcapsules are prepared consisting of 10-80 mg propranolol HCl or 25-100mg atenolol and 0.25-1.0 mg scopolamine HBr per dose. The inactiveingredients are selected from starch as the binding agent, mannitol as asweetener, diluent, and dispersant, and sodium bicarbonate as a bufferand dispersant. Magnesium stearate may help in flow of the powder,especially in tablet-making using a mechanical tablet press. Apreservative agent may be included in the formulation.

Tablets are formed by compression of the powder using a mechanicaltablet press. For instance tablets without coatings are prepared withcomposition #11 at about 70 mg each, for use as sublingual or oral doseforms. At this size of tablet an adult dose would deliver 20 mgpropranolol HCl and 0.5 mg scopolamine HBr. Alternatively, tablets maybe produced using a triturate tablet mold (e.g., from the vendor PCCA),wherein the triturated powder is moistened with 95% ethanol and then thewells are filled with the moistened composition, extruded from thewells, and dried. The sublingual tablets dissolve rapidly under thetongue, for instance in less than one minute (e.g., solid dose forms #13and 14). Propranolol HCl manifested an “acidic” and “medicine” taste aswell as delayed paresthesia of the tongue in humans, whereas atenolollacked these undesirable characteristics (i.e., comparison of solid doseforms #13 vs. 14). Sublingual (or buccal) tablets may be preferred forrapid disintegration, dissolution, absorption and increasedbioavailability via the mucosal route. A sublingual tablet of #23weighing ca. 82 mg delivers a dose of ca. 25 mg atenolol and ca. 0.25 mgof scopolamine HBr. Tablets may also be ingested orally, although it isrational to presume that absorption will be somewhat delayed andbioavailability will be somewhat reduced with many APIs, relative to themucosal route.

As an alternative to tablets, gelatin capsules (or other biocompatibleand biodegradable capsules) may be filled with the powder. Gelatincapsules may be selected to disintegrate or dissolve rapidly, forinstance within 15 minutes or more preferably within 5 minutes in thestomach. Gelatin capsules would likely delay, albeit slightly, theabsorption and pharmacologic effects, relative to a comparable uncoatedtablet or liquid dose form. When “time is of the essence” forsymptomatic treatment a gelatin capsule would not be preferred.

The preferred routes of delivery for solid compositions are oral andsublingual, although in certain circumstances tablets may be used inother mucosal routes of delivery. In an embodiment, taste-maskingflavors and sweeteners other than mannitol, or in addition to mannitol,may be included in the formulation. Powders may be dispensed inpre-dosed quantities to be mixed into a drink (e.g., water) foringestion. Powders intended for ingestion might not require starch oranother binding agent. Tablets may be ingested orally or applied to theoral mucosal for sublingual (or buccal) delivery. Capsules (e.g., gelcapsules) filled with the pharmaceutical composition may be ingestedorally or opened to pour the powder into a drink.

A buffering agent or agents (e.g., bicarbonate or phosphate) may beincluded in formulations to increase and buffer the pH to that of theoral cavity (˜6.2-7.4) for sublingual and/or buccal delivery. Abuffering agent or agents might be included for oral medications (e.g.,tablets or powders), although it should be noted that the stomachenvironment is acidic. Alkaline compositions could benefit from the useof an organic acid (e.g., citric acid) or buffer.

In other solid compositions, one may substitute other beta blockers inlieu of propranolol HCl or atenolol and/or other antiemetic muscarinicreceptor antagonist agents in lieu of scopolamine HBr.

Example 4 Method of Treating

Due to their high degree of pharmacologic activity and their lowtoxicity, together presenting a most favorable therapeutic index, theactive principles of the present invention are administered to asubject, e.g., a living animal (including a human) body, in needthereof, for the treatment, alleviation, amelioration, palliation, orelimination of a symptom or an indication or a condition which issusceptible thereto, or representatively of an indication or conditionset forth elsewhere in this application, preferably concurrently,simultaneously, or together with one or more pharmaceutically-acceptableexcipients, carriers, or diluents, especially and preferably in the formof a pharmaceutical composition thereof, whether by oral, sublingual,buccal, rectal, vaginal, transdermal, or parenteral route, in aneffective amount. Suitable dosage ranges are 0.1-400 milligrams,preferably 0.1-200 milligrams, and especially 0.1-100 milligrams,depending as usual upon the historic dosages in humans for theindividual APIs (albeit in combination) and the exact mode ofadministration, form in which administered, the indication toward whichthe administration is directed, the subject involved and the body weightor surface area of the subject involved, and the preference andexperience of the physician or veterinarian in charge. The active agentsof the present invention are administered orally, mucosally (e.g.,buccally, by nasal inhalation, or rectally), topically, or parenterallyin dosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers. It may be desirable to use themucosal route to hasten the pharmacologic effects. Furthermore, it maybe desirable to use the oral route.

As disclosed herein, the dose of the components in the compositions ofthe present invention is determined to ensure that the dose administeredwill not exceed an amount determined after consideration of either thehistoric dosing of the APIs in humans and the individual conditions of apatient, or the results obtained in test animals. A specific dosenaturally varies depending on the dosage procedure, the conditions of apatient or a subject animal such as age, body weight, sex, sensitivity,feed, dosage period, drugs used in combination, seriousness of thedisease. The appropriate dose and dosage times under certain conditionscan be determined by the test based on the above-described indices butmay be refined and ultimately decided according to the judgment of thepractitioner and each patient's circumstances (age, general condition,severity of symptoms, sex, etc.) according to standard clinicaltechniques.

Toxicity and therapeutic efficacy of the APIs either alone or incompositions of the present invention can be determined by standardpharmaceutical procedures in experimental animals, e.g., by determiningthe LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween therapeutic and toxic effects is the therapeutic index and itcan be expressed as the ratio ED₅₀/LD₅₀. APIs and/or compositions thatexhibit large therapeutic indices are preferred.

Example 5 Mode of Treatment of Patients Affected by PA, PD, Anxiety,Anxiety-Related Disorders, and Other Psychiatric Disorders

The present invention provides a self-administered p.r.n. symptomatictherapy taken by a patient in need thereof at the time of an episode ofPA or anxiety, or in anticipation of a panic or anxiety episode, or atthe time of a “trigger” circumstance for PA or anxiety. Thepharmaceutical composition having an effective amount of a combinationof an antimuscarinic drug and a beta adrenergic receptor antagonist drugis administered and temporarily alleviates some of the symptoms of PA,PD, agoraphobia, generalized anxiety disorder, social anxietydisorder/social phobia, performance anxiety, and/or PTSD at the time ofa symptomatic episode or in anticipation of an episode.

Of the various anxiety-related disorders, it may be preferable to treatsocial anxiety disorder/social phobia and performance anxiety with thecompositions of the present invention.

Compositions of the present invention may also be of value as asupportive p.r.n. therapy during cognitive behavioral therapy (CBT) orother forms of counseling for anxiety and panic patients. Thecompositions may provide anxiolytic benefit without cognitive impairmentwhile learning or reinforcing desirable behaviors. The dual drugtherapies may also be used when the patients experience acute anxietyepisodes between sessions of CBT or other forms of counseling.

The symptoms which are alleviated by the combination therapy of anantimuscarinic drug and a beta adrenergic receptor antagonist druginclude tachycardia, increased blood pressure, palpitations, nausea,vomiting, mental anxiety, fear, aberrant breathing (dyspnea andhyperventilation), sweating, trembling (tremors), migraine, headache,and post-traumatic stress. The present invention stops or diminishes theseverity of one or more of these somatic and/or psychic symptoms. Thepresent invention produces a calming effect in individuals, as discernedby the treated individual and/or observed by an objective observer.

The patients at the time of an episode of PA or anxiety or inanticipation of an episode of PA or anxiety may self-medicate by mucosal(e.g., sublingual, buccal, rectal, vaginal, or nasal) or oral routes,using the pharmaceutical compositions of the invention. Mucosal routesof drug delivery provide more rapid relief of symptoms compared toorally-ingested pharmaceutical compositions. Mucosal routes abrogatefirst-pass metabolism by the liver. Therefore, sublingual/buccal (orother mucosal) routes of administration provide immediate or moreimmediate relief when a patient has an episode of PA or anxiety, as wellas in abrogating an episode of PA or anxiety upon encountering a triggercircumstance in advance of the expected symptoms.

The patients are treated p.r.n. sublingually or orally with solid dosecompositions (e.g., tablets) consisting essentially of scopolamine at˜0.1-0.5 mg in combination with atenolol at ˜25-50 mg or propranolol at˜20-40 mg, as representative examples. Other combinations of APIs anddoses are also envisioned. Patients will experience beneficialabrogation or reduction in somatic and/or psychic symptoms of PA, PD,anxiety, or an anxiety disorder. The treatment provides an anxiolyticand/or calming effect. The beneficial effects (and side effects, if any)are hastened by the sublingual route of administration relative to anoral route of administration. As a specific example, a healthy adultsubject administered sublingual atenolol plus scopolamine in tabletform, and at another time a sublingual propranolol plus scopolamine intablet form. In each case a calming effect commenced in less than 15minutes and lasted for multiple hours in duration, and without sedation.Dryness of the mouth was a side effect.

The dual drug approach is superior to treatments by thealternatives—most notably benzodiazepines (as well as opioids, opiates,or cannabinoids), especially given that the APIs of the presentinvention are non-addicting and not Controlled Substances that are oftenabused.

Patients affected by psychiatric disorders (beyond panic and acuteanxiety) such as alcohol addiction and/or withdrawal, drug addictionand/or withdrawal, migraine, headache, and aggression are treated withsimilar dual-drug medications or two APIs in separate compositionsconcomitantly. In some instances these diverse psychiatric disorders areco-morbid with one another and/or share in common a set of symptoms.Upon administration, the dual-drug compositions affect a diversity ofsymptoms, such as tachycardia, increased blood pressure, palpitations,nausea, vomiting, mental anxiety, fear, dyspnea, hyperventilation,migraine, headache, sweating, trembling, avoidance, post-traumaticstress, drug dependence, alcohol dependence, restlessness, irritability,and aggression. The dual-drug approach, for instance scopolamine plus abeta blocker (e.g., atenolol or propranolol), affects most or all of thesymptoms typically associated with PA, PD, anxiety, and anxietydisorders that are coincident with the other psychiatric conditions.Additional benefits may extend to other symptoms not typicallyassociated with PA, PD, anxiety, or anxiety-related disorders.Furthermore, an anxiolytic or calming effect diminishes the number andmagnitude of the symptoms experienced in the psychiatric disorders.Thus, somatic and psychic (CNS) symptoms will be affected by thedual-drug therapies of the present invention.

Example 6 Clinical Trials

Clinical trials are designed to study the combination therapies of thepresent invention. One type of trial design is termed as “in life”usage. The patients at the time of an episode of PA or anxiety, or inanticipation of an episode, or at the time of a “trigger” circumstanceself-medicate by administering a pharmaceutical composition consistingessentially of an antimuscarinic drug and a beta adrenergic receptorantagonist drug and record by written or electronic means their specificsymptoms of episodes, number and severity of symptoms of episodes,timing and frequency of use of the therapy (either at onset or inanticipation of), perceived benefits, perceived side-effects, etc. Thepatient's self-assessment(s) at specified time points can include analog(e.g., visual analog scale) or digital (e.g., binary or discrete unitscale) assessment tools.

This “in life” trial design mimics how the combination therapy is usedin normal settings in a patient's life. The trials are “open label” indesign, where the identity of the therapy is disclosed to the physiciansand patients. Alternatively, a placebo of similar physical properties,yet lacking the APIs, is used as a control in “blinded” studies. In thelatter case the patients can also undergo a cross-over trial design, inwhich the first period of time is on either the therapy or the placebo.Then, during the next period of time the patient is switched over to thealternative. The results are collected at later time points and analyzedby statistical methods to demonstrate efficacy and/or safety of thepharmaceutical compositions of the invention.

An alternative clinical trial design is the Trier Social Stress Test(TSST) to provoke anxiety. This method is used in a clinic and involvessubjecting an individual to public speaking and mathematics questions asstressors. This approach has been used to study the effects of oralpropranolol in volunteer subjects [25-28].

An alternative clinical trial design involves the intentional chemicalprovocation of a panic attack in a clinic. Several methods ofprovocation of PA have been reported, wherein a physician intentionallystimulates a physiologic response by: (a) sodium lactate infusion [90,91]; (b) CO₂ inhalation [92]; and (c) cholecystokinin tetrapeptide(CCK-4) [90, 93]. These chemical exposures are used as tools to designcontrolled studies with predictable levels of PA episodes.

Patients afflicted by PA, PD, anxiety, or an anxiety disorder areenrolled in a provocation study (e.g., either TSST or chemicalprovocation). A placebo of similar physical properties, yet lacking theAPIs, is used as a control in “blinded” studies. In the case ofsublingual delivery (or other mucosal route) the drug or placebo isadministered ˜30 minutes prior to assessment, and in the case of oraldelivery the drug or placebo is administered ˜60 minutes prior toassessment. Alternatively, the trials are “open label” in design, wherethe identity of the therapy is disclosed to the physicians and/orpatients. The clinical endpoints are selected from the following list:heart rate, palpitations, blood pressure (especially systolic),respiratory rate (dyspnea and hyperventilation), tremors, mentalanxiety, fear, avoidance, nausea, migraine, headache, task performance,etc. The assessments of psychic anxiety can be assessed by theState-Trait Anxiety Inventory (STAI) or other similar tools [94, 95].The results are collected in the clinic and analyzed by statisticalmethods to demonstrate efficacy and/or safety of the pharmaceuticalcompositions of the invention.

Clinical trials are designed for patients affected by other psychiatricdisorders, beyond PA, PD, anxiety and anxiety disorders—such as alcoholaddiction and/or withdrawal, drug addiction and/or withdrawal, migraine,headache, and aggression. The studies are conducted either “in life”(e.g., “open label” use of the compositions) or in a clinic setting.When desired, the trials may be placebo controlled and blinded to theinvestigators and/or patients. The preferred dosing is p.r.n., as thecompositions are intended for occasional use in real life settings.

A patient affected by one or more of the psychiatric disordersself-administers either mucosally (e.g., sublingually) or orally acomposition consisting essentially of scopolamine HBr (e.g., atpreferably ca. 0.1-0.5 mg) in conjunction with a beta blocker (e.g.,atenolol at preferably ca. 25-50 mg or propranolol HCl at preferably ca.20-40 mg). Within an hour or less the patient and/or observer perceivesbenefit(s) with regard to symptoms. The therapeutic benefit(s) persistfor multiple hours, for example, as long as 6 hours or even 24 hours.Following treatment the patient experiences an anxiolytic or calmingeffect that results in the perception of relief from anxiety, inaddition to a reduction in cardiovascular symptoms (e.g., elevated heartrate, palpitations, and elevated blood pressure) due to epinephrine inthe circulation. These benefits can be achieved at doses of the APIsthat are non-sedating. The anxiolytic or calming effect can improvevoluntary and involuntary motor control, task performance, cognition,memory, avoidance of harm or danger, and/or reduce fear in patientsaffected by the other psychiatric disorders. The benefit of the dualdrug approach is superior to an antiemetic antimuscarinic therapy aloneor a beta blocker therapy alone. Dryness of the mouth may occur as aside effect in some patients due to the antiemetic antimuscarinic agent(and especially so with sublingual delivery).

Example 7 Physicians' Prescriptions and Commercial Use

Prior to this present invention there were no commercial drug productsavailable as combination therapies consisting essentially of a betablocker plus an antiemetic antimuscarinic for the p.r.n. treatment ofthe symptoms of psychiatric disorders or conditions, or any medicalcondition for that matter. Therefore, an example of the utility andbenefits of the present invention is physician prescriptions written bypaper or electronic means for combination therapies for the treatment ofthe symptoms of PA, PD, anxiety, and anxiety disorders, and subject tothe compositions and methods of the present invention.

Within the USA, it is anticipated that the combination therapies wouldtypically require prescriptions under Federal and/or State laws, unlessdeemed as non-prescription OTC products. Physician prescriptions provideevidence of a physician's professional judgment as a licensed healthcareprovider of the anticipated efficacy and safety of the combinationtherapies. The physician's prescription is also an evidence of apatient's desire and/or need for treatment, as applicable in individualsafflicted by the conditions of PA, PD, anxiety, and other psychiatricdisorders. Furthermore, commercial sales of the prescription products ofthe combination therapies by a pharmacy are an additional evidence ofthe utility and benefits of the present invention.

Prescriptions and commercial sales of the pharmaceutical compositions ofthe present invention have recently commenced in the USA (albeitfollowing the Priority Date of filing with the USPTO). Solid dose formscontaining combinations of atenolol plus scopolamine, as well aspropranolol plus scopolamine, have been prescribed by licensed medicalprofessionals. Furthermore, the combination drug products have beendelivered to the human patients, who were deemed by the licensed medicalprofessionals to be in need of p.r.n. anxiolytic treatments by the oraland/or sublingual routes of administration. Thus, examples of thepharmaceutical compositions of the present invention have recentlyentered into commercial use in the USA.

Outside of the pharmaceutical compositions of the present invention,rapid-acting sublingual (or other mucosal) dose forms are notcommercially available for either beta blockers or antimuscarinicagents. Beta blockers are readily available as oral solid dose forms.With regard to antimuscarinic agents, scopolamine is routinelyprescribed as a topical patch in the USA, and multiple antiemeticantimuscarinic drugs are sold as oral (solid or liquid) dose forms.Thus, for the first time in commercial use the present invention hasprovided a dual drug combination approach to p.r.n. anxiolytic therapy,as well as non-oral routes of delivery.

Example 8 Patient Treatment

A patient diagnosed with and/or affected by PA, PD, anxiety, or ananxiety disorder is beginning to experience symptoms of a PA or acuteanxiety (e.g., elevated heart rate, palpitations, or nausea) andself-administers p.r.n. a pharmaceutical composition consistingessentially of propranolol and scopolamine or atenolol and scopolamine.Some or all of the symptoms associated with a PA, PD, anxiety, or ananxiety disorder are suppressed and/or alleviated in the patient. Themedication produces an anxiolytic and/or calming effect.

Example 9 Patient Treatment

A patient diagnosed with and/or affected by PA, PD, or anxiety isexposed to a trigger circumstance (e.g., flying, a crowd, or a noise)that has formerly resulted in a PA or anxiety and immediatelyself-administers p.r.n. a pharmaceutical composition consistingessentially of propranolol and scopolamine or atenolol and scopolamine.With or without treatment there may be a delay between encountering thetrigger circumstance and the anticipated symptoms of PA or anxiety. As aresult of treatment, some or all of the symptoms associated with PA oranxiety are prevented and/or alleviated in the patient. The medicationproduces an anxiolytic and/or calming effect.

Example 10 Patient Treatment

In certain panic- and acute anxiety-prone patients the pharmaceuticalcompositions of the invention consisting essentially of anantimuscarinic drug and a beta adrenergic receptor antagonist drug aresublingually or orally administered in advance of an anticipated triggeror symptoms of a PA or acute anxiety. When the patient anticipates atrigger or symptoms in 15-60 minutes in the future, then self-medicationis started 15-60 minutes prior to the expected trigger or symptoms.Furthermore, when “time is of the essence” the mucosal route(s) ofdelivery are preferred (e.g., sublingual). For instance, if a patientdesires the effect of the medication in 30 minutes or less, the mucosalroute(s) of delivery are preferred, whereas if the patient desires theeffect beyond 30 minutes then the oral route of delivery may bepreferred. It follows that an oral gelatin capsule would delay somewhatthe therapeutic benefits, and is not preferred for rapid therapy.

The efficacious benefit of a single administered dose will last forhours, provided sufficient blood levels of the antimuscarinic and/or theanti-beta adrenergic APIs are sustained. The overt effects of a singledose may diminish over the course of a day, as the APIs areprogressively metabolized and/or excreted. Note that both scopolamineand propranolol are metabolized by the liver, whereas atenolol is not.Thus, an impairment of hepatic functions might prolong the effects ofthe certain drug combinations. The blood levels of the APIs areinfluenced by multiple pharmacologic and physiologic parameters, such asabsorption, distribution, metabolism, and excretion (ADME), as well asother individual patient genetic and environmental conditions. Itfollows that the blood levels of the APIs are expected to vary somewhatfrom patient to patient. This variability could affect efficacy.

Example 11 Patient Treatment

Patients affected by psychiatric disorders beyond panic and anxiety,such as alcohol addiction and/or withdrawal, drug addiction and/orwithdrawal, migraine, headache, and aggression are treated in a similarmanner using the pharmaceutical compositions of the present invention.Following treatment the patient experiences an anxiolytic and/or calmingeffect that results in the perception of relief from anxiety, inaddition to a reduction in cardiovascular symptoms (e.g., elevated heartrate, palpitations, and elevated blood pressure) due to epinephrine inthe circulation. The anxiolytic or calming effect may improve cognition,memory, voluntary and involuntary motor control, task performance,avoidance of harm or danger, and/or may reduce fear in patients affectedby the other psychiatric disorders. The dual-drug approachcoincidentally reduces the number and/or severity of the symptomsassociated with these disorders. The benefit of the dual drug approachis superior to an antimuscarinic therapy alone or a beta blocker therapyalone. The dual drug approach is superior to treatments by thealternatives—benzodiazepines, opioids, opiates, or cannabinoids,especially given that the APIs of the present invention arenon-addicting and not Controlled Substances that are often abused.Dryness of the mouth may occur as a side effect in some patients.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description.

All patents, applications, publications, test methods, literature, andother materials cited herein are hereby incorporated by reference.

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The invention claimed is:
 1. A method for treating anxiety disorders orthe symptoms thereof, comprising administering to a living animal,including a human, a pharmaceutical composition consisting essentiallyof a therapeutically effective amount of a combination of at least onebeta adrenergic receptor antagonist agent and/or pharmaceuticallyacceptable salts thereof, and at least one antiemetic muscarinicreceptor antagonist agent and/or pharmaceutically acceptable saltsthereof.
 2. The method of claim 1, wherein the anxiety disorders areselected from the group consisting of panic attack, panic disorder,agoraphobia, anxiety, generalized anxiety disorder, social anxietydisorder, performance anxiety, and post-traumatic stress disorder. 3.The method of claim 1, wherein the symptoms of the anxiety disorders areselected from the group consisting of tachycardia, increased bloodpressure, palpitations, nausea, vomiting, mental anxiety, fear,avoidance, dyspnea, hyperventilation, migraine, headache, sweating,trembling, and post-traumatic stress.
 4. The method of claim 1, whereinthe at least one beta adrenergic receptor antagonist agent is selectedfrom the group consisting of propranolol, atenolol, Eucommia extract,and/or pharmaceutically acceptable salts thereof, and wherein the atleast one antiemetic muscarinic receptor antagonist agent is selectedfrom the group consisting of scopolamine, diphenhydramine, meclizine,and/or pharmaceutically acceptable salts thereof.
 5. The method of claim1, wherein the at least one beta adrenergic receptor antagonist agent ispropranolol or atenolol, and/or pharmaceutically acceptable saltsthereof, in an amount of about 10 to 100 mg/dose for an adult, andwherein the at least one antiemetic muscarinic receptor antagonist agentis scopolamine, and/or pharmaceutically acceptable salts thereof, in anamount of about 0.05 to 1.0 mg/dose for an adult, and wherein the dosesare lower for an adolescent or child.
 6. The method of claim 1, whereinthe pharmaceutical composition, when in liquid or semi-solid form,comprises at least one penetration-enhancing solvent selected from thegroup consisting of ethanol, glycerol, propylene glycol, ethoxydiglycol,and dimethylsulfoxide or, when in solid form, comprises at least oneadditional component selected from the group consisting of mannitol, amonosaccharide, a disaccharide, a bicarbonate buffer, a phosphatebuffer, a binding agent, and a preservative.
 7. The method of claim 1,wherein the pharmaceutical composition is in a form selected from thegroup consisting of a spray, an elixir, a solution, a suspension, anemulsion, a gel, a cream, a gum, a powder, a tablet, a capsule, atroche, a suppository, a pill, and a film, and wherein thepharmaceutical composition is administered to the animal, including ahuman, by a route of delivery selected from the group consisting ofmucosal, sublingual, buccal, rectal, vaginal, nasal, parenteral, oral,and topical routes.
 8. The method of claim 1, wherein the at least onebeta adrenergic receptor antagonist agent is propranolol, atenolol,pindolol, nadolol, or nebivolol and/or pharmaceutically acceptable saltsthereof, in an amount of about 10 to 100 mg/dose for an adult, andwherein the at least one antiemetic muscarinic receptor antagonist agentis scopolamine, and/or pharmaceutically acceptable salts thereof, in anamount of about 0.05 to 1.0 mg/dose for an adult, and wherein the dosesare lower for an adolescent or child, and wherein the pharmaceuticalcomposition is administered to the patient by a route of deliveryselected from the group consisting of mucosal, sublingual, buccal,rectal, vaginal, nasal, parenteral, and oral routes.
 9. The method ofclaim 1, wherein the pharmaceutical composition is administered pro renata (p.r.n.) to the animal, including a human, by a route of deliveryselected from the group consisting of mucosal, sublingual, buccal,rectal, vaginal, nasal, and parenteral routes for rapid therapeuticeffect commencing within 30 minutes or less, or by the oral route ofdelivery.
 10. The method of claim 1, wherein the at least one betaadrenergic receptor antagonist agent exerts therapeutic effects onsomatic cardiovascular symptoms of the anxiety disorders, and the atleast one antiemetic muscarinic receptor antagonist agent exertstherapeutic effects on somatic non-cardiovascular symptoms and/orcentral nervous system symptoms of the anxiety disorders.
 11. The methodof claim 1, wherein the pharmaceutical composition when administered tothe living animal, including a human, exerts dryness of the mouth as aside effect of the muscarinic receptor antagonist agent, and whereinthis side effect deters continuous or daily administration of thepharmaceutical composition in a human.